2-(Hydroxyalkyl)-cyclopentane carbaldehydes

ABSTRACT

Therapeutically useful cyclopentane derivatives, some of which are new, of the formula:   WHEREIN R1 is alkyl, alkoxyalkyl, cycloalkyl or adamantyl, R2 is hydrogen, alkyl or carboxylic acyl, R3 is carboxy, alkoxycarbonyl, carbamoyl, carbazoyl, or carbamoyl or carbazoyl substituted by alkyl, R4 is oxygen, hydroxyimino alkoxyimino, hydrazono or alkyl-substituted hydrazono, R5 is alkyl or hydrogen, X is trans-vinylene or ethylene, and n is 5,6,7 or 8, are prepared by a new process involving few steps and as intermediates new compounds of the formula:   WHEREIN A is a group   OR C NOR8, in which R7 is alkyl or the symbols R7 together represent an ethylene or alkyl-substituted ethylene linkage, and R8 is alkyl. The cyclopentane derivatives are useful in the production of hypotension, bronchodilation, inhibition of gastric acid secretion, and stimulation of uterine contraction.

United States Patent n 1 Caton et al.

1 Apr. 29, 1975 l l 2(HYDROXYALKYL)-CYCLOPENTANE CARBALDEHYDES [75]Inventors; Michael Peter Lear Caton.

Upminster'. Edward Charles John Coffee. London; Gordon Leonard Watkins,Hornchurch. all of England {73} Assignee: May & Baker Limited. Dagenham.

Essex, England [22] Filed: June 12. 1972 [21] App]. No: 261,719

[30] Foreign Application Priority Data June 14. 1971 United Kingdom .i27844/71 Jun. 25. 1972 United Kingdom 3455/72 [52] U.S. C1 U 260/340);260/468 D; 260/468 J; 260/468 K; 260/468 L; 260/514 D; 260/514 .1;260/514 K: 260/514 L; 260/566 AE;

[51] Int. Cl C07d 13/04 Field of Search .l 260/3409 598 [561 ReferencesCited UNITED STATES PATENTS 3.402.181 9/1968 Erickson et a1 260/340,?

Primary Bram/nur-Donald G. Duus Assixlrm! ExuminurRaymond V RushAlmrnvy. Agent, or FirmStevens. Davis Miller &

Mosher 1 1 ABSTRACT Therapeuticully useful cyclopcntune derivatives.some of which are new. of the formula:

----(CH R 4L- cH-Rl wherein R is alkyl, alkoxyalkyl, eycloalkyl oradamantyl, R is hydrogen, alkyl or carboxylic ucyl, R is carboxy,alkoxycarhonyl, carbumoyl. carhazoyl, or carbamoyl or carhazoylsubstituted by ulkyl, R is oxygen. hydroxyimino alkoxyimino. hydruzonoor 2lll( \lsubstituted hydrazono. R is ulkyl or hydrogen. X istrzins-vinylene or ethylene, 11nd n is 567 or 8.21m prepared by a newprocess involving few steps and us in termediates new compounds of theformula:

wherein A is a group CHO 4 Claims, No Drawings2-(HYDROXYALKYLl-CYCLOPENTANE CARBALDEHYDES (wherein R, represents astraightor branched-chain alkyl group containing from 1 to carbon atoms,which may be substituted by an alkoxy group, or represents a cycloalkylgroup containing from 5 to 7 carbon atoms, or an adamantyl group, Rrepresents a hydrogen atom, an alkyl group, or a carboxylic acyl, forexample alkanoyl or benzoyl, group, R represents a carboxy group. astraightor branched-chain alkoxycarbonyl group containing from 1 to 12carbon atoms in the alkoxy moiety, or a carbamoyl or carbazoyl groupwhich is unsubstituted or substituted by one or two alkyl groups, R,represents an oxygen atom, a hydroxyimino or alkoxyimino group, or ahydrazono group which is unsubstituted or substituted by one or twoalkyl groups, R,-, represents an alkyl group or a hydrogen atom, Xrepresents a transvinylene or an ethylene group, and n represents 5,6,7or 8) and, when R represents a carboxy group. non-toxic salts thereof.

In this specification, it is to be understood that unless otherwisespecified, alkyl groups and alkyl moieties of alkoxy, alkanoyl andalkoxyimino groups may be straightor branched-chain and may contain from1 to 6 carbon atoms.

As will be apparent to those skilled in the art, the structure shown ingeneral formula 1 has at least three centres of chirality, two of thesethree centres of chirality being at the ring carbon atoms in positions 1and 2 respectively and the third being at the carbon atom in themethylidene group linking together the groups X, R, and CR In additionto these three centres of chirality, of course, a further centre ofchirality occurs at the ring carbon atom in position 4 when R representsan alkyl group and still further centres of chirality may occur in alkylgroups represented by, or present as moieties in the groups representedby, the symbols R,, R R R and R The presence of centres of chirality, asis well known, leads to the existence of isomerism. However, thecompounds of formula 1 produced by the process of the present inventionall have such a configuration that the side chains attached to the ringcarbon atoms in positions 1 and 2 are trans with respect to each other.Accordingly, all isomers of general formula 1, and mixtures thereof,which have those side chains, attached to the ring carbon atoms inpositions 1 and 2, in the trans configuration, are within the scope ofthe present invention.

It is known, for example from British Patent specification No. 1,097,533(The Upjohn Company) that the compound of general formula 1 wherein R,represents a pentyl group R represents a hydrogen atom, R represents acarboxy group, R represents an oxygen atom, R represents a hydrogenatom. n represents 6 and X represents a vinylene group, which may benamed as l5-hydroxy-9-oxoprost-l3-enoic acid, possesses valuablehypotensive and antihypertensive properties. In the said British PatentSpecification there is described a process for the preparation of thatparticular compound, which, as described, involves two reaction stepscommencing with, as starting material, the costly natural product 11,15-dihydroxy-9-oxoprost -1 3-enoic acid, which is alternatively knownas prostaglandin E or PGE In British Patent specification Nos. 1,179,489and 1,218,998 (Ayerst, McKenna & Harrison Limited) there is described analternative sequence of eighteen reaction steps for the preparation of7-[5-(3- hydroxyoct-l-enyl)-2-oxocyclopentyl]heptanoic acid, commencingwith two initial starting materials which are readily accessible, i.e.,ethyl 7-bromoheptanoate and the potassium salt of the enol tautomer of2- ethoxycarbonylcyclopentanone.

1n the specification of West German Offenlegungsschrift No. 1,953,232(Ayerst. McKenna & Harrison Limited) there is described inter alia thepreparation of cyclopentane derivatives of general formula I in which R.represents a straight-chain alkyl radical containing 2 to 7 carbonatoms, R represents a hydrogen atom. R represents a carboxy group or analkoxycarbonyl group containing from 1 too 3 carbon atoms in the alkylmoiety, R represents an oxygen atom, R represents a hydrogen atom, Xrepresents an ethylene group, and n represents 6, from bicycloheptanecompounds, which process initially involves the use of the sametypes ofstarting materials as mentioned above in respect of the processesdescribed in British Patent specification Nos. 1,179,489 and 1,218,998.

As a result of research and experimentation there has been discovered anew and improved process, which when applied to the production of7-[5-(3-hydroxyoctl-enyl)-2-oxocyclopentyl]heptanoic acid and relatedcompounds, possesses advantage over the processes disclosed in BritishPatent specification Nos. 1.097.553, 1,179,489 and 1,218,998 and WestGerman Offenlegungsschrift No, 1,953,232 in that it involves a smallnumber of reaction steps from inexpensive starting materials which arereadily available commercially or easily accessible by known methods.

The new process of the present invention employs as initial startingmaterials aldehydes of the general formula'.

n wherein R represents a hydrogen atom or a suitable acid labile groupand n is as hereinbefore defined. Suitable acid labile groups are thosewhich are easily removed by acid hydrolysis and do not cause sidereactions, eg the Z-tetrahydropyranyl group unsubstituted or substitutedby, for example, at least one lower alkyl group.

The process of the invention for the preparation of cyclopentanederivatives of general formula 1 wherein R, and n are as hereinbeforedefined, R represents a 3 4 hydrogen atom R represents a carboxy group Rrepcess involves only eight steps as depicted and uses relaresents anoxygen atom and X represents a vinylene tively inexpensive startingmaterials and is, in consegroup. including 7-[5-(3-hydroxyoct-l-enyU-2-quence, distinctly advantageous in relation to theoxocyclopentyl]-heptanoic acid. may be illustrated known processes forthe preparation of the same comschematically as follows: 5 pounds.

tca l ca on (CI-I CHO R enamine Ii III -(cm CH on tcn l ca oa 2 n 2 R 5--cn l v IV (Qi CH OH tca l ca ou R R c. C1-!C VI v11 0 A (on coon 2 n Rtat l cooa R R l {a 1 H VIII tca coon R (wherein R R R and n are ashereinbefore defin d The reaction of an aldehyde of formula ll and anenand A represents a group of the general formula: amine -gthe ph lin nain f a cyclopenta- R 0 0 03 none to yield the2-hydroxyalkylcyclopent-2-en-l-ones 7 7 II of formula lll is carried outin an inert organic solvent C or L for example an aromatic hydrocarbon(e.g. benzene) with continuous removal of water, preferably at 60l20C..followed by hydrolysis in aqueous acid XI XII conditions (eg withhydrochloric acid), preferably at wherein the symbols R representidentical alkyl ambient temperature, and then heating with an acid,groups, or together the groups R, form an ethylene (e.g. concentratedhydrochloric acid), preferably at linkage which is unsubstituted orsubstituted by identi- 6s about C, and preferably in an inert organicsolvent cal alkyl groups on each carbon atom, and R repre such as analcohol (e.gv butanol) to cause the double sents an alkyl group.Preferably the groups R together bond to migrate from the exocyclic tothe endocyclic form an unsubstituted ethylene linkage) This newproposition.

The hydroxyalkylcyclopent-Z-en-l-ones ot general formula III are reactedwith a source of hydrogen cyanide (e.g. acetone cyanohydrin) in thepresence of a base, for example an alkali metal carbonate (e.g. sodiumcarbonate), in an aqueous organic solvent, for example an aqueous loweralkanol (eg. aqueous methanol), preferably at 50l C. and advantageouslyat the reflux temperature of the solvent employed, to give ketonitrilesof formula IV.

The ketals of general formula V wherein A represents a group of formulaXI are prepared from the ketonitriles of formula IV by the applicationor adaptation of'known methods for the preparation of ketals fromketones, for example by the reaction of a compound of formula IV withthe appropriate alcohol or diol in the presence of an acidic catalyst,for example p-toluenesulphonic acid, with continuous removal of water.Advantageously the reaction is effected in the presence of an inertorganic solvent, for example an aromatic hydrocarbon (e.g. benzene), atan elevated temperature, such that the continuous removal of water iscarried out by means of a Dean and Stark apparatus. The oximes ofgeneral formula V wherein A represents a group of formula XII areprepared from the ketonitriles of formula IV by the application oradaptation of known methods for the preparation of oximes from ketones,for example by the reaction of a compound of formula IV with theappropriate alkoxyamine in the presence of base.

The compounds of general formula V are reduced in an inert organicsolvent, for example a lower dialkyl ether (e.g. diethyl ether),preferably at a temperature between 80C. and 30C., to compounds offormula VI by means of known complex metal reducing agents, preferably adialkylaluminium hydride (e.g. diisobutylaluminium hydride) in an inertorganic solvent, for example an aromatic hydrocarbon (e.g. benzene). The2-(hydroxyalkyl) cyclopentanecarbaldehydes of formula VI are newcompounds and are key intermediates of the new process of the invention.

Reaction of compounds of formula V1 with a hydrocarbylcarbonylmethylenetriphenyl or trialkylphosphorane of the general formula:

(Q P=CHCOR XI (wherein 0 represents a phenyl group unsubstituted orsubstituted by a lower alkyl group. or represents a lower alkyl group,preferably n-butyl, and R is as hereinbefore defined) in an inertorganic solvent (e.g. tetrahydrofuran preferably at a temperature of l00C. and advantageously at the reflux temperature of the reactionmixture, gives unsaturated ketones of formula VII.

These ketones are then oxidised, preferably in an inert organic solvent,by means of an agent known to convert terminal hydroxymeti'iyl tocarboxy without affecting carbon-carbon double bonds or the group A (forexample chromium trioxide and sulphuric acid in dimethylformamidepreferably at a temperature of5 to +l0C.) to give cyclopentanealkanoicacids of formula Vlll.

These cyclopentanealkanoic acids, preferably in an inert organicsolvent, for example a lower alkanol (e.g. ethanol), are reduced bymeans of an agent known for the reduction of oxo to hydroxy withoutaffecting carbon-carbon double bonds. preferably by a metal borohydride(eg sodium borohydride) optionally in the presence of a base, forexample an alkali metal hydroxide (eg, sodium hydroxide), to yield asproducts the (hydroxyalkenyl )-cyclopentylalkanoic acids of formula IX.

The ketals of general formula IX wherein A represents a group of formulaXI are then subjected to aqueous acid hydrolysis, for example withdilute aqueous hydrochloric acid at 45-70C., to yield as products the5-(3-hydroxyalkenyl)-Z-oxocyclopentylalkanoic acids of formula X.Advantageously. as will be apparent to those skilled in the art, thishydrolysis is carried out as part ofthe reaction step convertingcompounds of formula VIII to compounds of formula IX where the re ducingagent used is a metal borohydride, where during the operation ofacidifying the metal salt in order to isolate the acid of formula IX,the conditions are modified, ifnecessary, in order to effect thehydrolysis of the ketal to a ketone of formula X. This reduces the number of reaction steps, depicted in the reaction scheme above, from eightto effectively seven.

The oximes of general formula IX wherein A represents a group of formulaXII, which have not hitherto been described and are among the novelcompounds of general formula I, may be converted to compounds of formulaX by the application or adaptation of known methods for the conversionof oximes to ketones, for example, by treatment of an aqueous organicsolution of an oxime of formuoa IX, preferably in a mixture of aqueousacetic acid and dioxan, with an aqueous solution oftitanium trichlorideunder an atmosphere of nitrogen.

The enamines of cyclopentanones used as starting materials in theprocess of the invention may be prepared from the cyclopentanone andsecondary amine, preferably in an aromatic hydrocarbon solvent (e.g.benzene or toluene), by the method of G. Stork et.al., J. Am. Chem. Soc.1963, 85, 207. Preferred secondary amines are 5 or 6-memberednitrogen-containing secondary heterocyclic bases, which may carry in thering one or two additional hetero atoms selected from oxygen andnitrogen (e.g. morpholine). When the amine contains more than onenitrogen atom, one of the nitrogen atoms is secondary and the remainderare tertiary.

The aldehyde compounds of general formula Il may be prepared by theapplication or adaptation of known methods, or by a process whichcomprises the reaction of a nitrile of the general formula;

(wherein n and R are as hereinbefore defined) in an inert organicsolvent such as a lower dialkyl ether (e.g. diethyl ether) with adialkylaluminium hydride (e.g. diisobutylaluminium hydride) in an inertorganic solvent, for example an aromatic hydrocarbon (e.g. benzene),preferably at a temperature of to +30C.

Aldehydes of formula II, wherein the group R is an acid labile group,e.g. Z-tetrahydropyranyl. and is represented by the symbol R may also beprepared by oxidation of a compound of the general formula:

XIV

(wherein n and R are as hereinbefore defined) with analkylcyclopentanone enamine as initial starting material because thatwould be liable to lead to the formation of appreciable quantities ofS-lhydroxyalkyl)-2-alkyl-2- agent known to convert hydroxymethyl toformyl without affecting the ether linkage for example the complex ofsulphur trioxide with pyridine in dimethylsulphoxide at ambient temperature.

The nitriles of formula XIV are readily available commercially or easilyaccessible by known methods.

For the preparation of aldehyde compounds of gen eral formula ll whereinn represents 6. an advantageous alternative preparation is the cleavageof the commer cially available aleuritic acid (9.lO.l6-trihydroxyhexadecanoic acid) by known methods. for example with aqueoussodium periodatc preferably at l()l5C.. or with lead tetraacetate.Similarly. aldehydes of formula ll wherein n represents 5.7 or 8 can beprepared by the cleavage of compounds analogous to aleuritic acid.

Ketonitriles of formula W. wherein the group R is an alkyl group. moreparticularly a methyl group. and is represented by the symbol R n beingas hereinbefore defined. are preferably prepared by the alkylation ofcorresponding ketonitriles of formula W. wherein R represents a hydrogenatom. wherein the hydroxy group of the group (CH- .),,CH OH isadvantageously protected by means of a suitable protecting group. thesaid protecting group being subsequently removed by the application oradaptation of known methods. The said process possesses advantage overthe use of an alkylcyclopentanone enamine as initial starting materialbecause that would be liable to lead to the formation of appreciablequantities of S-(hydroxyalkylJ-Z- alkyl-Z- cyclopenten-l'ones inaddition to the required 2-(hydroxyalltyl)-5-alkyl 2-cyclopenten-l-onesof formula lll. thereby necessitating a separation of isomers at somestage in the reaction sequence.

Accordingly. ketonitriles of formula IV. wherein R represents an alkyl.preferably methyl. group. n being as hereinbefore defined. arepreferably prepared by the acid hydrolysis of compounds of the generalformula CH oR (wherein R, Rt. and n are as hereinbefore defined). forexample by means of a strong mineral acid. e.g.. perchloric acid. in thepresence of a lower alkanol. e.g. ethanol.

Compounds of formula XVI are preferably prepared by the alkylation ofcompounds of the general formula:

XVII

ide. in the presence of an inert polar organic solvent. for exampleacetone. or a lower alkanol. e.g. methanol or ethanol. and preferably atan elevated temperature. for example the reflux temperature ofthereaction mixturc.

Compounds of formula XVll are prepared by the re' action of compounds ofthe general formula:

fijdca l ca on (wherein R and n are as hereinbefore defined) with adialkyl oxalate of the general formula:

R OOC'COOR XX XIX drogen atom and n is as hereinbefore defined. by theapplication of known methods for the protection of a hydroxy group witha group R for example. when R represents a Z-tetrahydropyranyl group. bythe action of 3.4-dihydro-2H-pyran in the presence of an acid. forexample hydrochloric acid or toluene-psulphonic acid. The reaction isoptionally carried out in the presence of an inert organic solvent. forexample. benzene or chloroform. preferably at a temperature of 40 to C.

The hydrocarbylcarbonylmethylenephosphoranes of formula Xlll used in theabove process for reaction with the2(hydroxyalkyl)cyclopentanecarbaldehydes of formula V! to give theunsaturated ketones of for mula Vll may be prepared by the reactionbetween a halomethyl ketone of the general formula:

Z2-CH2CORI (wherein R is as hereinbefore defined and Z represents abromine or chlorine atom) and an appropriate triphenyl ortrialkylphosphine in a suitable organic solvent (e.g. chloroform) undera nitrogen atmosphere. preferably at a temperature of 20l0OC. andadvantageously at the reflux temperature of the reaction mixture.followed by reaction of the resulting Z-oxoalkylphosphonium halide withan inorganic base (e.g. aqueous sodium carbonate) at ambienttemperature.

It will be appreciated that the carboxy group of the compounds offormulae lX (wherein A represents a group of formula Xll) and X can beconverted by the application or adaptation of known methods intoderivatives thereof such as alkoxycarbonyl groups or carbamoyl orcarbazoyl groups unsubstituted or substituted by alkyl groups. that thecarbonyl group in the compounds of formula X can be converted by theapplication or adaptation of known methods into derivativcs thereof suchas oximes. alkoxyimines or hydrazones where the hydrazono groups areunsubstituted or substituted by one or two alkyl groups. that thehydroxy group in the compounds of formulae lX (wherein A represents agroup of formula Xll) and X can be converted by the application oradaptation of known methods to alkoxy or acyloxy groups. and that thevinylene group in the compounds of formulae IX (wherein A represents agroup of formula XII) and X can be reduced by the application oradaptation of known meth ods to an ethylene group. From compounds soobtained. other cyclopentanone derivatives of general formula I cansimilarly be prepared by the application or adaptation of known methods.

Thus. compounds of general formula I in which R represents analkoxycarbonyl group can be prepared by the reaction ofa correspondingcarboxylic acid of general formula I in which R represents a carboxygroup with an alcohol of the general formula:

(wherein R represents an alkyl group containing from l to 12 carbonatoms). an excess of which may be employed as solvent medium. in thepresence of an inorganic acid. e.g. hydrochloric acid or sulphuric acid.preferably at a temperature between 50 and 160C. and advantageously atthe reflux temperature of the reaction mixture. or. where R can berepresented by the formula -CHR R, (wherein the symbols R and R eachrepresent a hydrogen atom or a lower alkyl group). with a diazoalkane ofthe general formula:

u u 2 XXIII (wherein R and R are as hereinbefore defined) in an inertorganic solvent medium. preferably a dialkyl ether (e.g. diethyl ether).preferably at ambient temperature. Alternatively. a silver salt of suchcarboxylic acids of formula I can be reacted with an alkykl halide R lwherein 2,, represents a halogen atom and R is as hereinbefore defined.optionally in the presence of an inert organic solvent such as anaromatic hydrocarbon (e.g. benzene) at elevated temperature andadvantageously at the reflux temperature ofthe reaction mixture.

Amides of formula I. wherein R represents a car bamoyl groupunsubstituted or substituted by up to two alkyl groups. can be preparedby the application or ad' aptation of known methods. for example:

a. by the reaction of a compound of the general formula:

XXII

IZI H xx v (wherein R and R each represents a hydrogen atom or an alkylgroup) with a compound of the general forfined and R represents an alkylgroup containing from 1 to 12 carbon atoms) in an inert organic solvent.eg a lower alkanol (preferably ethanol) or benzene. preferably at atemperature of 5(l-l()()('. and advantageously at the reflux temperatureof the reaction mixture. optionally in the presence of a basic catalyst.for example an alkali metal alkoxidc. in a lower alkanol. e.g. sodiumethoxide in ethanol;

b. by the reaction of a compound of formula XXV with formamide or analkylated formamide in the presence ofa basic catalyst. eg sodiummethoxide. accord ing to the method described by Allred and Hurwitz. J.Org. Chem. 1965.30. 2376;

c. as a further alternative. the same such amides of general formula I.except for those wherein R represents a hydrogen atom. can be preparedby reacting a corresponding acid halide of the general formula:

(Ch CO4. R XXVI iIH 1 (wherein R,. R. R n. X and Z are as hereinbeforedefined and R represents an alkyl or an acyl. for example alkanoyl orbenzoyl. group) with a compound of formula XXIV. preferably at ambienttemperature and optionally in an inert organic solvent. for example adi(lower) alkyl ether.

Hydrazono-hydrazides of formula I. wherein R represents a carbazoylgroup unsubstituted or substituted by one or two alkyl groups. Rrepresents a hydrazono group unsubstituted or substituted by one or twoalkyl groups and R,. R R n and X are as hereinbefore defined. may beprepared by the application or adaptation of known methods. for exampleby the substitution of compounds of formula XXIV by compounds of thegeneral formula:

(wherein R and R are as hereinbefore defined) in the processes (a) and(c) immediately hereinbefore described for the preparation of amides offormula I.

Hydrazides of formula I. wherein R represents a car bazoyl groupunsubstituted or substituted by one or two alkyl groups. R represents anoxygen atom and R R R;,. n and X are as hereinbefore defined. may beprepared by the reaction of compounds of formula XXVll with compounds ofthe general formula:

(wherein R,. R- R:- .R R R n. X and Z are as hereinbefore defined) inconditions similar to those hereinbefore described for the preparationof amides by reaction of compounds of formula XXIV with compounds offormula XXV and XXVI by processes (a) and (c), followed by conversion tothe corresponding ketones in conditions similar to those hereinbeforedescribed for conversion of compounds of formula IX (wherein Arepresents a group of formula XI) to compounds of formula X.

Compounds of the formulae XXV. XXVI. XXVIII and XXIX may be preparedfrom compounds of the formulae IX or I by the application or adaptationof known methods,

Compounds of formula I. in which R represents an acyl group. can beprepared from corresponding alcohols of formula I. in which R representsa hydrogen atom. by the application or adaptation of known methods. forexample by reaction with the appropriate acid anhydride. preferably inthe presence of a base. e.g. pyridine. preferably at ambienttemperature. optionally in the presence of an inert organic solvent suchas an aromatic hydrocarbon (e.g. benzene).

Compounds of formula I. in which R represents an alkyl group and Rrepresents an alkoxycarbonyl group wherein the alkyl moiety correspondsto R- can be prepared by the reaction of compounds of formula IX.wherein A preferably represents a group of formula XI. with a compoundof the general formula:

Y XXX (wherein R represents an alkyl group containing from I to (1carbon atoms. and Y represents the acid residue of a reactive ester. ega bromine. chlorine or iodine atom or a sulphonate or sulphate group);or alternatively with a compound of formula XXIII and a Lewis acid. e.g.boron trifluoride. in an inert organic solvent medium. preferably adialkyl ether (eg. diethyl ether). and preferably at a temperaturebetween 50 and +20C.'. to give compounds wherein R represents a group ofthe formula CHR R (wherein R and R are as hereinbefore defined).followed by conversion to the corresponding ketones in conditionssimilar to those hereinbefore described for conversion of compounds offormula IX to compounds of formula X.

Ketones of formula I. in which R represents an oxy gen atom. can beconverted to their derivatives. such as oximes. alkoxyimines andhydrazones which may be substituted by one or two alkyl groups. by theapplication of adaptation of known mehods. for example by reaction withthe appropriate hydroxylamine. alkoxya-- mine or hydrazine or alkylatedderivative thereof.

Compounds of formula I wherein X represents an ethylene group. R R R R Rand n being as hereinbefore defined. may be prepared. for example. by reduction of the corresponding compounds of formula I wherein X representsa vinylene group. by the application or adaptation of known methods. forexample by hydrogenation in the presence of a hydrogenation catalyst.e.g. palladium on charcoal. optionally under an elevated pressure.

Compounds offormula I wherein R represents a carboxy group may beprepared by alkaline hydrolysis of corresponding compounds of formula Iwherein R represents an alkoxycarbonyl group.

By "non-toxic salts" of the cyclopentanone derivatives of generalformula I wherein R represents a carboxy group is meant salts thecations of which are relatively innocuous to the animal organism whenused in therapeutic doses so that the beneficial pharmacolog icalproperties of the parent compound of general formula I are not vitiatedby side-effects ascribable to those cations. Preferably. the salts arewater-soluble, Suitable salts include the alkali metal. eg sodium orpotassium. and ammonium salts and pharmaceuticallyacceptable (i.e.non-toxic) amine salts.

Amines suitable for forming such salts with carboxylic acids are wellknown and include. for example. amines derived in theory by thereplacement of one or more of the hydrogen atoms of ammonia by groups.which may be the same or different when more than one hydrogen atom isreplaced. selected from alkyl groups containing from I to 6 carbonatoms. hydroxyalkyl groups containing from I to 3 carbon atoms.cycloalkyl groups containing from 3 to 6 carbon atoms. phenyl groups.phenylalkyl groups containing from 7 to II carbon atoms and phenylalkylgroups containing from 7 to 15 carbon atoms wherein the alkyl moietiesare substituted by hydroxy groups.

The phenyl groups and phenyl moieties of phenylalkyl groups may beunsubstituted or substituted by one or two alkyl groups containing fromI to 6 carbon atoms. Suitable amines also include those derived intheory by the replacement of two of the hydrogen atoms of ammonia by ahydrocarbon chain, which may be interrupted by nitrogen. oxygen orsulphur atoms. to form. together with the nitrogen atom of ammonia towhich its terminal groups are attached. a fiveor sixmemberednitrogen-containing heterocyclic ring. which heterocyclic ring may beunsubstituted or substituted by one or two alkyl groups containing fromI to 6 carbon atoms. Examples of suitable amine cations include mono-.diand tri-methylammonium. mono. diand tri-ethylammonium, mono. diandtripropylammonium. mono. diand triisopropylammonium.ethyldimethylammonium. monodiand tri-2hydroxyethylammonium. ethylbis(2-hydroxyethyhammonium. butylmono(Z-hydroxyethyl- )ammonium.tris(hydroxymethyl)ammonium. I-ethyl- 2-methylpiperidinium.cyclohexylammonium. benzylammonium. benzyldimethylammonium.dibenzylammonium. phenyl-'l-hydroxyethylammonium. piperidinium.morpholinium. pyrrolidinium. piperazinium. l-methylpiperidinium. 4-ethylmorpholinium. I-isopropylpyrrolidinium. 1.4- dimethylpiperazinium.l-butylpiperidinium. 2- methylpiperidinium and l.3-dihydr0xy-2-hydroxymethylprop-Z-ylammonium.

The non-toxic salts may be prepared by reaction of stoichiometricquantities of compounds of general formula I wherein R represents acarboxy group and the appropriate base. e.g. an alkali metal hydroxideor carbonate. ammonium hydroxide. ammonia. or an amine. in a suitablesolvent which is preferably water in the case of the preparation ofalkali metal salts and water or isopropanol in the case of ammonium oramine saltsv The salts may be isolated by lyophilisation of thesolution. or. if sufficiently insoluble in the reaction me dium, byfiltration. if necessary after removal of part of the solvent.

By the term known methods as used in this specification is meant methodsheretofore used or described in the literature.

In the aforementioned British Patent specifications Nos. I.U97.533 andI.2I8.998 and in US. Pat. Nos. 3.501.525 and 3.504.020 (M. Lapidus etal. assignors to American Home Products Corporation) there are disclosedthose compounds of formula I wherein the various symbols R,. R R;,. R.,.R.-,. n and X have the following values simultaneously: R, represents ann-pentyl group. R represents a hydrogen atom or an alkanoyl group. Rrepresents a carboxy group or an alkoxycan bonyl group wherein thealkoxy moiety contains from I to 10 carbon atoms. R, represents anoxygen atom, R represents a hydrogen atom. n represents 6 and Xrepresents a transvinylene or ethylene group. and when R represents acarboxy group. salts thereof.

in West German Offenlegungsschrift No. 1.953.232 there are disclosedthose compounds of formula I wherein the various symbols R,. R R,,. R,.R n and X have the following values simultaneously: R, repre sents astraight-chain alkyl group containing from 2 to 7 carbon atoms. Rrepresents a hydrogen atom or an acyl group. R,, represents a carboxygroup or an alkoxy carbonyl group wherein the alkoxy moiety containsfrom I to 3 carbon atoms. R, represents an oxygen atom. R represents ahydrogen atom. n represents 6 and Z represents an ethylene group.

According to a feature of the present invention there are provided novelcompounds of formula I which have not been described hitherto. Amongthese novel compounds of formula I there are the following compounds offormula I which are outside the scope disclosed in any of theabove-mentioned patents and patent appli cation of the prior art:

a. all those compounds of formula I wherein at least one of the symbolsR,. R R,,. R,. R and n has a significance as specified below:

R, represents a methyl group. an alkyl group containing 8. 9 or carbonatoms. a branched-chain alkyl group containing from 2 to 7 carbon atoms.or an alkoxyalkyl. cycloalkyl or adamantyl group;

R represents an alkyl group; R represents a carbamoyl or carbazoyl groupwhic is unsubstituted or substituted by one or two alkyl groups. or analkoxycarbonyl groups wherein the alkoxy moiety contains 1 l or 12carbon atoms;

R. represents a hydroxyimino or alkoxyimino group. or a hydrazono groupwhich is unsubstituted or substituted by one or two alkyl groups;

R represents an alkyl group;

n represents 5. 7 or 8; and. where R represents a carboxy group.non-toxic salts thereof. the significance of the other symbols R,, R RR,, R n and X being as hereinbefore defined with reference to formula I;

b. non-toxic salts of all those compounds of formula I wherein R,represents a straight-chain alkyl group containing 2. 3. 4, 6 or 7carbon atoms, R represents a hydrogen atom or an acyl group. Rrepresents a car boxy group. R, represents an oxygen atom. R representsa hydrogen atom. n represents 6 and X represents an ethylene group.

c. all those compounds of formula I wherein R, represents astraight-chain alkyl group containing 2. 3. 4. 6 or 7 carbon atoms. Rrepresents a hydrogen atom or an acyl group. R, represents an oxygenatom. R represents a hydrogen atom and n represents 6 and at least oneofthe symbols R and X has a significance as specitied below:

R represents an alkoxycarbonyl group wherein the alkoxy moiety containsfrom 4 to 12 carbon atoms;

X represents a trans-vinylene group; the significance of the othersymbol R,, or X being as hereinbefore defined with reference to formulal.

Other novel compounds of formula l are compounds specifically describedin the present specification which. although they are within the scopedisclosed in one or more of the abovementioned patents and patentapplication ofthe prior art. have not hitherto been specificallydescribed. These novel compounds are: 7-[5-(3-hydroxyhex-l-enyl)-2-oxocyclopentyllheptanoic acid.7-l5-(3-hydroxyhept-l-enyl)-2-oxocyclopentyl]- heptanoic acid. 7[5-(3-hydroxynon-l-enyll2-oxocyclopentyllheptanoic acid.7-l5-(3-hydroxydec-l-enyll- 2-oxocyclopentyllheptanoic acid and 2a-(6carboxyhexyl)-3B-(3B-hydroxyoct-l-enyl)- cyclopentanone which lastcompound has not hitherto been described as separated from itsdiastcreoisomer. 20z( carboxyhexyl )-3/3-( 3a-hydroxyoctl -enyl)cyclopentanone.

The novel compounds of the present invention pos sess valuablepharmacological properties including. in particular. the production ofhypotension. bronchodilation. inhibition of gastric acid secretion. andstimulation of uterine contraction. in laboratory screening tests thecompounds produce:

a. a IOmmHg fall in the mean blood pressure of theurethane-anaesthetised. pempidine-treated normotensive rat at dosesbetween 0.0005 and 2.0 mg/kg animal body weight administeredintravenously;

b. a 50 percent inhibition of the bronchoconstriction induced byadministration of a bronchoconstrictor agonist. e.g. histamine or5-hydroxytryptamine. in the urethane-anaesthetised guinea pig whenadministered intravenously at doses between 0.005 and ug/kg animal bodyweight;

0. a 50 percent inhibition of pentagastrin-induced gastric acidsecretion in the rat at doses of between 1.0 and 100 pg/kg animal bodyweight/minute when administered orally in solution in an aqueous sodiumchloride solution;

d. a l00 percent increase in amplitude of contraction of the uterus ofthe pregnant rat when administered intravenously at doses between 0i andl0 mg/kg body weight.

Especially useful are those compounds of formula I and. when Rrepresents a carboxy group. non-toxic salts thereof. in which R, is asecondary alkyl group. that is to say R, is branched at the carbon atomby which it is attached to the group CHOR and in particular7-[5-(3-hydroxy-4-methyloct-l-enyl)-2-oxocyclopentyllheptanoic acid andits non-toxic salts. which are all novel compounds and which exhibit inparticular high bronchodilator activity in association with a reducedlevel of hypotensive activity. and are therefore particularly useful asbronchodilators in conditions where the production of a hypotensiveeffect is contraindicated.

Among the other important compounds of the present invention are thefollowing compounds: 7-[5-(3- hydroxy-S-methylhexl -enyl)-2-oxocyclopentyl lheptanoic acid. 7-[543cyclopentyl-3-hydroxyprop-lenyl )-2-oxocyclopentyl ]heptanoic acid. 7-[5'( 3- hydroxydodec-l-enylJ-Z-oxocyclopentyl]heptanoic acid.7-[5-(3-hydroxy-5-methyloct-l-enyl) 2-oxocyclopentyll-heptanoic acid.7-[5-(3-hydroxy-6- methyloct-l-enyl)-2-oxocyclopentyllheptanoic acid.7-[5-(3-hydroxy-7-methyloct-l-enyl)-2-oxocyclopen tyllheptanoic acid. 7[5 (3-cyclohexyl-3-hydroxyprop- 1-enyll-2-oxocyclopentyl]heptanoic acid.7-[5-(3- hydroxy-S-methoxyoctl -enyl i-2-oxocyclopentyllheptanoic acid.7-[5-(3-adamantyl-3-hydroxyprop l 15 enyl l-Z-oxocyelopentyl lheptanoicacid. 7-l5-( 3- cyclopentyl-3-hydroxyprop-lyll-loxocyclopentyllheptanoicacid, 7l5-(3-hydroxyoct-l-enyll-3-methyl- Z-oxocyclopentyllheptanoicacid, 7-[ 2 methoxyimino -(3 hydroxyoet-lenyl)cyclopentyllheptanoicacid. 7-1 5-( 3-acetoxy-4methyloct-1 enyl)-2-oxocyclopentylI-heptanoicacid. methyl 7-[5( 3-cyclohexyl-3-hydroxyproplenylJ-Z-oxocyclopcntyl]heptanoate. methyl7{5-(3-cyelopentyl3 hydroxypropl-enyl)-2- oxocyclopentyl l-heptanoate.methyl 7-154 3- hydroxydodec-1-enyll-Loxocyclopentyllheptanoate.N-methyl-7-[5-(3-hydroxydodec-l-enyl)'lomcyclopentyllheptanoamide andheptyl 7-15-(3- cyclohexy l-3-hydroxypropl 'enyl )-2-oxocyclopentylheptanoate.

As will be readily appreciated by those skilled in the art. the isomericforms of the compounds of the invention arising from the aforementionedcentres of chirality may be separated by the application or adaptationof known methods, for example diastereoisomeric forms may be separatedby chromatography using selective adsorption from solution or from thevapour phase onto suitable adsorbents, and enantiomeric forms of acidiccompounds of formula l wherein R represents a carboxy group may beseparated by formation of salts with an optically active base. followedby separation of the obtained pair of diastereoisomers by. for example.fractional crystallisation from a suitable solvent system. followed byseparate regeneration of the enantiomeric acids of formula I.

The following Examples illustrate the present invention.

EXAMPLE l 7-[ 5-( 3-Hydroxy-4-methyloctl-enyl)-2-ococyclopentyll-heptanoic acid i. Preparation of2-(7-hydroxyhcptyl)cyclopent-Z-em l-one A mixture of7-(2-tetrahydropyranyloxy)heptanal (22 g.) and l-morpholinocyclopentene,i.e.. the morpholine enaminc of cyclopentanone. (21.4 g.) in benzene (25ml.) was heated under reflux for 12 hours under nitrogen. and the waterliberated was continuously removed with a Dean and Stark head. Benzeneml.) and then, dropwise, 18 percent hydrochloric acid (28 ml.) wereadded and the mixture was stirred for 2 hours The organic layer wasseparated and evaporated. Concentrated hydrochloric acid (72 ml.) andbutanol (300 ml. were added to the residue. The mixture was heated at100C. for 1 hour. and then the solution was concentrated to give an oil.Diethyl ether was added. and the ether solution was washed with aqueoussodium bicarbonate and then water. and dried over sodium sulphate. Thesolvent was evaporated and the residue was distilled under reducedpressure to give 2-( 7- hydroxyhcptyl)cyclopent-IZ-en-l-one 11.7 g.).b.p. l-l70C/0.15 mm.Hg. m, 1.490, A ,,,,,,228mp. (ethanol).

The 7-(2-tetrahydropyranyloxy)heptanol used as starting material in theabove procedure was prepared as follows:

3.4-Dihydro-2H-pyran (272 g.) was added dropwise at 40C. with stirringto a mixture of 7- hydroxyheptanenitrilc (284 g.) and concentrated bydrochloric acid (10 drops). The temperature was allowed to rise to 65C.and was maintained at this level for one hour. The solution was cooledand and benzene (500 ml.) was added. The solution was washed withaqueous sodium bicarbonate and then water. and dried over sodiumsulphate. The solvent was removed in vacuo. and the residue distilledunder reduced pressure to give 7-( 2-tctrahydropyranyloxy)heptanenitrile (41 l g). b.p. l00-130C./0.l mmHg. n,, "1.455.

Diisobutylaluminium hydride (19.4 g.) in dry benzene (50 ml.) was addeddropwise at 10C. to a stirred solution of7-(2-tetrahydropyranyloxytheptanenitrile (20.6 g.) in dry diethyl ether(200 ml.). The solution was stirred at 10C. for 30 minutes and was thenadded to 2N aqueous sulphuric acid (300 ml.) at 0C. The mixture washeated at 30C. for 30 minutes. and then saturated with sodium chlorideand the layers were separated. The aqueous layer was extracted withdiethyl ether and the combined organic layers were washed with aqueoussodium bicarbonate. and then aqueous sodium chloride. and dried oversodium sulphate. The solvent was evaporated and the residue wasdistilled under reduced pressure to give 7-( 2-tetrahydropyranyloxy)-heptanal 12.7 g.) b.p. 78l06C./0.1 mmHg, n 1.456.

The above procedure may also be carried out replacing the7(Z-tetrahydropyranyloxy )heptanal by 7- hydroxyheptanal (prepared asdescribed above for 7- (2tetrahydropyranyloxy)heptanal. but using 7-hydroxyheptanenitrile in place of 7-( 2tetrahydropyranyloxy)-heptanenitrile].

Advantageously. 7-hydroxyheptanal can be prepared in one step fromaleuritic acid using the method de scribed below.

Sodium hydroxide (13.2 g.) in water (660 ml.) was added to aleuriticacid (100 g.) and the suspension stirred at 0 to 10C. To the resultingsuspension of sodium aleuritate was added sodium periodate (80 g.) inwater (800 m1.) over 1 hour. without allowing the temperature to riseabove 15C. Diehloromethane (200 ml.) was then added and the mixturestirred for a further 2.5 hours at 15C. A further amount of dichloromethane (300 ml.) and saturated aqueous sodium bicarbonate ml.) wereadded and the mixture vigorously stirred. The precipitated sodium iodatewas removed by filtration and the dichloromethane layer separated. Theaqueous phase was washed with dichloromethane (500 ml.) and the combineddichloromethane extracts dried over anhydrous magnesium sulphate.Removal of the dichloromethane in vacuo below 40C. gave7-hydroxyheptanal (43 g.).v,,,,,, 3400 cm, 2700 cm. 1710 cm".

ii. Preparation of 2-(7-hydroxyhcptyl)-3-oxocyclopentanecarbonitrile Amixture of 2 (7-hydroxyheptyl)cyclopent-Z-enl-one (17 g.). acetonecyanohydrin (8.5 g. I. 6 percent aqueous sodium carbonate (8 ml.) andmethanol (50 ml.) was stirred and heated under reflux for 4 hours.Methanol was removed in vacuo. water 100 ml.) was added and the mixturewas extracted with diethyl ether and dried over magnesium sulphate. Thesolvent was removed by evaporation. and the residue was distilled underreduced pressure to give Z-t7hydroxyheptyl)-3-oxocyclopentanecarbonitrile (13.3 g. 144-182C./0.15 mm.Hg. m 1.4795.

iii. Preparation of 7-cyano-6 (7-hydroxyheptyl)-l .4-dioxaspiro[4.4]nonane A mixture of 2(lhydroxyheptyl)Jcxocyclopentanecarbonitrile (20 g. ethylene glycol (5.6 g. p-tol uenesulphonic acid(I g.) and benzene ml.) was heated to reflux for 3 /2 hours withcontinuous removal of water. The mixture was cooled to ambienttemperature. anhydrous sodium carbonate was added. and after Found:(ISHZHNOII C, 67. l; requires:

iv. Preparation of 7-formyl-6-(7-hydr0xyheptyl)-1.4-dioxaspiro[4.4]nonane A solution of diisobutylaluminum hydride (53 g.)in dry benzene (145 ml.) was added. with rapid stirring. to a solutionof 7-cyano-6-( 7 hydroxyheptyl)-l .4-dioxaspiro[4.4]nonane (43.2 g.) indry diethyl ether (432 ml.) at l-l5C. Stirring at ambient temperaturewas continued for l hours and the mixture was added to 2N aqueous aceticacid (l litre) at a temperature lower than C. The organic phase wasseparated and the aqueous layer was extracted with diethyl ether. Thecombined organic phases were washed with aqueous sodium bicarbonate,dried over sodium sulphate. the solvents removed in vacuo and theresidue distilled under reduced pressure to give 7-formyl-6-(7-hydroxyheptyl)-l.4-dioxaspiro[4.4]nonane (25.3 g.). b.p.l64200C./0.04-0.05 mm.Hg.v,,,,,, l7l0 cm", 2700 om 1 (liquid film).

v. Preparation of 6-(7-hydroxyheptyl)-l.4-dioxa-7-(3-oxo-4-methyloct-l-enyl)spiro[4,4]nonane.

A mixture of 7-formyl-6-(7-hydroxyheptyl)-l .4-dioxaspiro[4,4]nonane(3.88 g.) and 2- methylhexanoylmethylenetriphenylphosphorane (6.0 g.) indry tetrahydrofuran ml.) was heated to reflux under nitrogen for l8hours. The solvent was removed in vacuo and the residue triturated withpetroleum ether (b.p. 60-80C.). allowed to stand at 0C., filtered toremove triphenylphosphine oxide and the filtrate evaporated to give6-(7-hydroxyheptyl)-l.4-dioxa-7-(3-oxo-4-methyloct-l-enyl)spiro[4.4]nonane (5.56 g.),v,, 1620cm", 1660 cm". This material was used for the next step, the preparationof 7-{l .4 dioxa-7-( 3-oxo-4-methyloctl-enyl)spiro[4.4 ]non-6-yllheptanoic acid. without further purification being necessary.

2-Methylhexanoylmethylenetriphenylphosphorane. used as startingmaterial. was prepared as follows:

A solution of lchloro-3-methylheptan-2-one (49.4 g.) andtriphenylphosphine (79.5 g.) in chloroform (250 ml.) was saturated withnitrogen and refluxed under nitrogen overnight. The chloroform wasremoved in vacuo and the residue (crude 2-oxo-3-methylheptyltriphenylphosphonium chloride) was added portionwise to asolution of sodium carbonate (109 g.) in water (i500 ml.) and themixture was stirred vigorously for 24 hours. The solution was extractedwith diethyl ether. and the ethereal extracts were dried over magnesiumsulphate. The solvent was removed by evaporation and the residue wascooled and triturated with petroleum ether (b.p. 6080C.) to give2-methylhexanoylmethylenetriphenylphosphorane (35.2 g). m.p. l07l09C.

l-Chloro-3-methylheptan-2-one. used as starting material. was preparedas follows:

2-Methylhexanoyl chloride (42.5 g.) was added dropwise at 40C. to asolution of diazomethane (24 g.) in diethyl ether (600 ml.) and thesolution was stirred for 1 hour at ambient temperature. Hydrogenchloride gas was then bubbled into the solution until it was fullysaturated. Crushed ice was added to give approximately l litre ofaqueous solution. The organic layer was separated and the aqueous layerwas ex tracted with diethyl ether. The combined organic layers weredried over magnesium sulphate. evaporated, and the residue distilledunder reduced pressure to give l-chloro-3-methylheptan-2-one (49.5 g),b.p. l00-l l0C./l 3 mm.Hg. vi. Preparation of7-{l.4-dioxa-7-(3-oxo-4-methyloctl-enyl)spiro[4.4]non-6-yl}heptanoicacid Chromium trioxide (6.0 g.) (dried over phosphorus pentoxide) wasadded portionwise with stirring to a solution of6-(7-hydroxyheptyl)-l.4-di0xa-7-(3-oxo-4-methyloct-l-enyl)spiro[4.4]nonane (5.56 g.) in dry dimethylformamide (70ml.) at a temperature lower than 0C. Concentrated sulphuric acid (2 ml.)in dimethylformamide (70 ml.) was added and the mixture stirred at below10C. for 1 hour. Diethyl ether was added followed by a minimum quantityof water to produce two readily separable layers. The ether layer wasseparated and stirred with aqueous 2N sodium carbonate solution. Theaqueous layer was separated. washed with diethyl ether. and then coveredwith a layer of diethyl ether and acidified to pH4 by the dropwiseaddition of concentrated hydrochloric acid. The ethereal layer wasseparated and the aqueous layer again extracted with diethyl ether. Thecombined ethereal layers were dried over sodium sulphate and evaporatedto give crude 7- {l,4-dioxa-7-( 3-oxo-4-methyloctl -enyl )spirol 4.4]-non-6-yl} heptanoic acid (l.4 g.). v,,,,., 1620 cm". [660 cm. [700 cm.This material was used for the next step. the preparation of7-[5-(3-hydroxy-4- methyloct-l-enyl)-2-oxocyclopentyl]heptanoic acid.without further purification being necessary. vii. Preparation of7-[5-(3-hydroxy-4 methyloct-lenyl)-2-oxocyclopentyllheptanoic acid Asolution of sodium borohydride (0.07 g.) in 0.2N aqueous sodiumhydroxide (0.7 ml.) was added dropwise to a solution of7-{1.4-dioxa-7-(3-oxo-4- methyloct-l-enyl)spirol4.4]non-6-yl heptanoicacid (0.7 g.) in ethanol (10 ml.) and N sodium hydroxide (0.65 ml.). Theresulting solution was stirred for 4.5 hours and then the ethanolremoved in vacuo. Water [0 ml.) was added, the solution washed withdiethyl ether and the aqueous layer was covered with a layer of diethylether and acidified to pH] by the dropwise addition of concentratedhydrochloric acidv The ether layer was separated and the aqueous layerwas extracted twice more with diethyl ether. The combined ether extractswere dried over magnesium sulphate and the solvent evaporated. A mixtureof the residue and 2N hydrochloric acid 10 ml.) was heated to -75C. withstirring for 1.2 hours. The cooled mixture was extracted twice withdiethyl ether and the combined extracts dried (magnesium sulphate) andevaporated. The residue was purified by preparative thin-layerchromatography on silica gel using a 65:15:] mixture of benzene, dioxaneand acetic acid as eluent to give7-l5-(3-hydroxy-4-methyloct-l-enyl)-2-oxocyclopentyl]heptanoic acid(0.33 g.) Elemental analysis:

Found; C. 71.8: H. 10.2%;

EXAMPLE 2 7-[ 5( 3-Hydroxyoctl -enyl )-2-oxoc yclopentyl lheptanoic acidi. Preparation of 6-(7-hydroxyheptyl)-l.4-dioxa7-(3- oxoctl-enyl)spirol-l.4]nonane A mixture of 7-formyl-6-( 7-hydroxyheptyl)-l.4-dioxaspirol4.4]nonane (69.) prepared as described in Example l) andhexanoylmethylenetriphenylphosphorane (8.5 g.) in dry tetrahydrofuran(50 ml.) was heated to reflux under nitrogen for 16 hours. The solventwas removed in vacuo and the residue triturated with petroleum ether(b.p. 6080C.), cooled to 0C. for l day. filtered to removetriphenylphosphine oxide and the filtrate evaporated. The residue wasagain triturated with petroleum ether (b.p. 60-80C.) to remove furthertriphenylphosphine oxide. filtered and evapo rated to give6-(7-hydroxyheptyl)-l .4-dioxa-7-(3- oxooct-Lenyl)-spirol4.4]nonane (7.5g.). v 1620 cm". l660 cm".

Hexanoylmethylenetriphenylphosphorane, used as starting material. wasprepared as follows:

A solution of l-chloroheptan2-one (33 g.) and tri phenylphsophine (60g.) in chloroform (50 ml.) was saturated with nitrogen and refluxedunder nitrogen overnight. The chloroform was removed in vacuo and theresidue was dissolved in dichloromethane (l50 ml. Dry diethyl ether (600ml.) was added to precipitate Z-oxoheptyltriphenylphosphonium chloride(60 g.) m.p. l65l68C. This compound (23 g.) was added portionwise to asolution of sodium carbonate (25 g.) in water (250 ml.) and the mixturewas stirred vigorously for 24 hours. The solution was extracted withdiethyl ether. and the ethereal extracts were dried over magnesiumsulphate. The solvent was removed by evaporation and the residue wascooled and triturated with petroleum ether (b.p. 4060C.). The solid thusobtained was recrystallised from petroleum ether (b.p. 6080C.) to givenexanoylmethylenetriphenylphos-- phorane (l7 g.). m.p. 7374C.

ii Preparation of 7- {l.4dioxa-7-(3-oxooct l enyl)-spiro{4.4lnon-o-yllheptanoic acid Chromium trioxide (2.80 g.) (driedover phosphorus pentoxide) was added portionwise with stirring to asolution of6-(7-hydroxyheptyl)-l.4-dioxa-7-(3oxooctlenyllspirol4.4]nonane (2.5 g.)in dry dimethylformamide (40 ml.) at a temperature lower than 0C. Coneentrated sulphuric acid (1 ml.) in dimethylformamide ml.) was added andthe mixture stirred at below 0C. for l5 minutes. Diethyl ether (50 ml.)was added followed by a minimum quantity of water to produce two readilyseparable layers. The ether layer was separated. dried over magnesiumsulphate and evaporated to give crude 7- {l .4-dioxa-7-( 3-oxooctlenyl)spiro(4.4]non'6-yl}heptanoic acid (2.23 g.). This material was usedfor the next step. the preparation of 7-l 5-( 3-hydroxyoct-l-enyl)-2-oxocyclopentyl]heptanoic acid. without further purification beingneces sary. iii. Preparation of 7-[5( 3-hydroxyoctl-enyl)-2-oxocyclopentyl1heptanoic acid A solution of sodium borohydride(0.54 g.) in 0.2N aqueous sodium hydroxide (5.4 ml.) was added dropwiseto a solution of 7- {l .4-dioxa-7-( 3-oxooct-lenyl)spiro[4.4]non-6-yl}heptanoic acid (2.23 g.) in ethanol (54 ml) and N sodium hydroxide (5.4ml.). The resulting solution was stirred for l day and then the ethanolremoved in vacuo. The aqueous layer was covered with a layer of diethylether and acidified to pHl by the dropwise addition of concentratedhydrochloric acid. The ether layer was separated and the aqueous layerwas extracted twice more with diethyl ether. The combined ether extractswere dried over magnesium sulphate and the solvent evaporated. A mixtureof the residue (1.09 g.). water (5 ml.) and 2N hydrochloric acid (10ml.) was heated to C. with stirring for 3 hours. The cooled mixture wasextracted twice with diethyl ether and the combined extracts dried(magnesium sulphate) and evaporated. The residue (0.89 g.) was purifledby preparative thin-layer chromatography on silica gel using a :15:]mixture of benzene. dioxane and acetic acid as eluent to give7-[5-(3-hydroxyoct-lenyl)-2-oxocyclopentyllheptanoic acid, (0.7 g.).Elemental analysis:

Found: ZII ILl J C. 70.7; H. 109?: requires; C. 70,96; H. l0.l2. r; v980 cm"v 1700 cm 1720 cm".

EXAMPLE 3 7 l S-( 3-Hydroxy-5-methylhexl -enyl)-2-ox0cyclopentyll-heptanoic acid C. 80.3: requires:

used as a starting material in the above preparation, iv

was prepared in a similar manner to that described above in Example 2(i)for the preparation of hexanoylmethylenetriphenylphosphorane, butsubstituting l-chloro-4-methylpentan-2-one (prepared according to themethod described by Azinger et al, Annalen, (1964). 672. 156) for thel-chloroheptan-2-one. (The melting point of the intermediate 4-methyl-2-oxopentyltriphenylphosphonium chloride was 208C. ii. Preparation of7-{7-(5-methyl-3-oxohex-l-enyl)- l.4-dioxaspiro[4.4]non-6yl}heptanoicacid in a similar manner to that described above in Example 2(ii) forthe preparation of 7-{L4-dioxa-7-(3- oxooct-l-enyl)spirol4,4]non-6-yllheptanoic acid, but substituting the appropriate quantity of 6-(7-hydroxyheptyl )-7( 5-methyl-3-oxohexl enyl )-l .4- dioxaspiro[4.4lnonanefor the 6-(7-hydroxyheptyl)- l.4-dioxa-7-( 3-oxooctl -enyl)spiro[4,4]nonane. there was prepared7-{7-(5-methyl-3-oxohex-l-enyl)-l,4- dioxaspirol4.4l-non-6-yl}heptanoicacid. iii. Preparation of7-l5-(3-hydroxy-5-methylhex-lenyl)-2oxocyclopentyl]heptanoic acid In asimilar manner to that described above in Example 2(iii) for thepreparation of 7[5-(3-hydroxyoct-lenyll-l-oxocyclopentyllheptanoic acid.but substituting the appropriate quantity of 7-{7-(5-methyl-3- oxohex l-enyl )-1 .4-dioxaspiro[ 4,4 lnon-oyl}heptanoic acid for the 7-{l.4-dioxa-7-(3-oxooct-lenyl)spiro[4,4]-non-6-yl} heptanoic acid. therewas prepared 7-(5-( 3-hydroxy5-methylhex l -enyl )-2-oxocyclopentyHheptanoic acid. v,,,,, 980 cm. 1700 cm", l720 cm. NMR(approximately percent so lution in deuterochloroform); doublet at 0.98(.1 =6 cycles/second). multiplets at 1.555, 2.02.66, 5.65. broadmultiplet at 3.76-4155, singlet at 7.455.

Elemental analysis:

Found: C. 69.9; H. 9.7%; c.3 0. requires: C. 70.3: H. 99%.

EXAMPLE 4 7-[ 5-( 3-Cyclopentyl-3-hydroxypropl -enyl)-2-oxocyclopentyl]heptanoic acid Found: Zh 'M requires: H. 6.7?!

used in the above preparation. was prepared in a similar manner to thatdescribed above in Example 2(i) for the preparation ofhexanoylmethylenetriphenylphos phorane, but substituting chloromethylcyclopentyl kctone [prepared according to the method described byMousseron et al. Bull. Soc. Chim. France. (1952). 767 and Comptes Rendusl95 l 232, L562. with the modification of using hydrogen chloride gasinstead of concentrated hydrochloric acid] for the lChlOI'OhCPIkU'I-2-one. (The melting point of the intermediate 2-cyclopentyl-2-oxoethyltriphenylphosphonium chloride was 160C). ii.Preparation of7-{7-(3-cyclopentyl-3-oxoprop-lenylJ-l.4-dioxaspiro[4.4lnon-o-yllheptanoicacid In a similar manner to that described above in Exam ple 2(ii) forthe preparation of 7-{l.4-dioxa-7-(3- oxooct-l-enyl)spiro[4.4]non-6-yllheptanoic acid, but substituting the appropriate quantity of 7-( 3-cyclopentyl-3-oxopropl-enyl )-6-( 7-hydroxyheptyl l,4-dioxaspiro[ 4,4]nonane for the 6-( 7hydroxyheptyl)-l,4-dioxa-7-(3-oxooct-lenyl)spiro[4.4]nonane, the e wasprepared 7-{7-(3- cyclopentyl-3-oxopropl -cnyl l .4-dioxaspirol 4,4non-b-yllheptanoic acid. This material was used for the next step. thepreparatifin of 7-[5-(3-cyclopentyl-3- hydroxypropl -enyl)-2-o'.ocyclopentyl ]-heptanoic acid. without further p'l'rificationbeing necessary.

iii. Preparation of7-[5i.3-cyclopentyl-3-hydroxypropl-enyl)-2-oxocyclopeni 'llheptanoicacid In a similar manner to that described above in Example 2(iii) forthe preparation of 7-[5-(3-hydroxyoct-lenyl)-2-oxocyclopentyl]heptanoicacid, but substituting the appropriate quantity of 7-{7-(3-cyclopentyl-3- oxoprop- 1 -enyl l 4-dioxaspirol 4.4 ]non-b-yl}-heptanoic acid for the 7{l .4-dioxa 7-(3-oxooct-lenyl)-spiro[4.4]non-6-yl} heptanoic acid. there was prepared7-[5-(3-cyclopentyl-3-hydroxyprop-l-enyl)- 2-oxocyclopentyl]heptanoicacid. u 1725 cm". l700 cm. 980 cm.

Elemental analysis:

Found: C. 7l.l; Hv 9.492; C H O. requires: C. 71.4; H 9.547.

EXAMPLE 5 The 7-[5-(3-hydroxy-4-methyloct-l-enyl)-2-oxocyclopentyl]heptanoic acid (0.30 g), prepared as described in Example l,was further purified and separated into two diastereoisomeric componentsby pre parative thin-layer chromatography on silica gel using a 40:40:]mixture by volume of ethyl acetate. cyclohexane and formic acid as theeluent. The chromatogram was eluted with the solvent mixture four times.allowing it to dry at room temperature after each elution. The positionsofthe two bands were then detected by spraying a small strip of thechromatogram with a solution of phosphomolybdic acid in ethanol 10percent w/v) and the remainder of each band was then removed from thesupporting glass plate and extracted with diethyl ether using a Soxhletapparatus. Evaporation to dryness of the ether extracts gave twodiastereoisomeric components of 7-[5-(3-hydroxy-4-methyloctl-enyl)-2oxocyclopentyll-heptanoic acid. designated "component 5a" (closer to theorigin on the chromatogram; 80 mg.) and component 51)" (further from theorigin on the chromatogram; mg.) respectively. NMR data for component 5a(approximately [0 percent solution in deuterochloroform) includedmultiplets at 0.65-1.055, 1.05-2.76. 3.75-4.28. 545-5706 and a singletat 4.968.

The NMR data for component 51) were sensibly iden' tical except that thesinglet (attributed to hydrogen atoms in hydroxy and carboxy groups)occurred at 5. l 8 instead of at 4.968.

EXAMPLE 6 By proceeding in a manner similar to that described in Example5 and using an identical solvent mixture as eluent.7-[5(3-hydroxyoct-l-enyl)-2-oxocyclopentyl]- heptanoic acid (0.30 g.).prepared as described in Example 2, was separated into two components(presumed to be diastereoisomeric pairs of enantiomers) by preparativethin-layer chromatography on silica gel. designated component 6a(further from the origin in the chromatogram; 50 mg.) and component 6b"(closer to the origin in the chromatogram; 40 mg.) respectively.

The NMR data for the two components were sensibly identical(approximately l0 percent solution in deuterochloroform )z multiplets atl 05 2.06.

2.0-2.78, 3.854r35 and 5.455.705, singlet at 6.655, and a triplet at0.898.

One component was the novel diastereoisomer. 2a- (o-carboxyhexyl )3B-(3B-hydroxyoctl -enyl )cyclopentanone. and one component was the knowndia- 23 ste reoisomer. 2a-( b-carboxyhexyl )-3{3-( 3ahydroxyoctl -enyl)cyclopentanone.

EXAMPLE 7 7-( 5( S-Hydroxynonl -enyl )Q-oxocyclopentyl ]heptanoic acidi. Preparation of o-(7-hydroxyheptyl)-l.4-dioxa-7(3- oxononl enyl)spiro[4.4 lnonane By proceeding in a similar manner to that describedin Example 1(v) for the preparation of 6-(7- hydroxyh'eptyl I.4-dioxa-7-( 3-oxo4 methyloct l enyll-spirol4.4lnonane. but substitutingthe appropriate quantity of heptanoylmethylenetriphenylphosphorane forthe 2-methylhexanoylmethylenetriphenylphosphorane used as a startingmaterial. there was prepared crude6-(7-hydroxyheptyl)-l.4-dioxa-7(3-oxonon-lenyll-spiro[4.4]nonane. pureenough for use as starting material in the preparation of 7-{1.4-dioxa7-(3- oxonon l-enyl)-spiro[4.4]non-6-yl} heptanoic acidhereinafter described.

The heptanoylmethylenetriphenylphosphorane (mp. 8788C.. elementalanalysis:

C. 79.9; H. requires C.

Found:

c a ov H. 7.450. I.

used as a starting material in the above preparation. was prepared in asimilar manner to that described in Example l(v) for the preparation of2- methylhexanoylmethylenetriphenylphosphorane. but substituting theappropriate quantity of l-chlorooctan- Z-one (prepared as described byArcher. Unser and Froelich. J. Amer. Chem. Soc.. 1956. 78. 6182) for thelchloro-3-methylheptan-2-one used as a starting material. The meltingpoint of the intermediate 2- oxooctyltriphcnylphosphonium chloride wasl79-l 81C. ii. Preparation of 7-(l,4-dioxa-7-(3-ox0non-l enyllspiro[4.4Inonb-yllheptanoic acid By proceeding in a similar manner tothat described in Example 1(vi] for the preparation of 7- {l.4-dioxa 7--(3-oxo-4-methyloctl -enyl )spirol4.4 lnon-fi-yl} heptanoic acid. butsubstituting the appropriate quantity of 6-(7-hydroxyheptyl1-l.4dioxa-7-(3-oxonon-l entyl)-spirol4.4lnonane for the 6-(7-hydroxyheptyl)-l.4-dioxa 7(3'oxo-4-methyloct-lenyl)spiro[4.4]nonane used as a startingmaterial. there was prepared7-{1.4-dioxa-7-(3-oxononlenyl)spiro[4.4]non-6-yl heptanoic acid. v,,,,,,1620 cm". 1660 cm". 1700 cm". iii. Preparation of7-[5-(3-hydroxyn0n-l-enyH-2- oxocyclopentyllheptanoic acid By proceedingin a similar manner to that described in Example 1(vii) for thepreparation of 7-[5-(3- hydroxyA-methyloct-l-enyl)-2-oxocyclopentyl]-heptanoic acid. but substituting the appropriate quantity of7-{l.4-dioxa-7-(3-oxonon-l-enyl)spiro(4.4lnon-dyll-heptanoic acid forthe 7-{l.4-dioxa-7-(3-oxo-4-methyloct-l-enyl)spiro[4.4lnon-b-yllheptanoic acid used as astarting material. there was prepared 7- [5-(3hydroxynon-l'enyll-2-oxocyclopentyllheptanoic acid.

Elemental analysis:

Found: il lw l NMR (approximately 10 percent solution indeuterochloroformztriplet at 0.98(] 5.5 cycles/second). multiplets at1.05-2.08, 2.0-2.78, 3.94.48, 5.25-5.758 and a broad singlet at 7.048.

EXAMPLE 8 By proceeding in a manner similar to that hereinbe foredescribed in Example 2(iii) for the preparation of 7-[ 5( 3-hydroxyoctl-enyll-2-oxocyclopentyl lheptanoic acid, but substituting the7-{l.4-dioxa-7-(3- oxooct-l-enyl)spiro[4.4lnon--yllheptanoic acid usedas starting material by the appropriate quantities of 7- {l.4-dioxa-743-oxodecl-enyl)spiro[4.4]non- 6-yl}-heptanoic acid.

7- {l .4-dioxa-7-( 3oxododecl -enyl )spiro[4.4 ]non (a-yll-heptanoicacid,

7- ll .4-dioxa-7-( B-oxoheptl -enyl )spiro[ 4,4 lnon fa-yll-heptanoicacid.

fi-yll-heptanoic acid.

dioxaspiro [4.4] non-6-yl}heptanoic acid. 7-l7-(6-methyl-3-oxooctl -enyll .4-

dioxaspirol4.4lnon-6-yllheptanoic acid.

dioxaspirol4.4]non-6-yl}heptanoic acid.7-{7-(3-cyclohexyl-3-oxoprop-l-enyl)-1.4-

dioxaspirol4.4lnon-6yl}heptanoic acid.

dioxaspiro{4.4]-non-6-yll heptanoic acid respectively (which wereprepared as hereinafter described). there were prepared 7-1543-hydroxydecl-enyl)-2oxocyclopentyl]heptanoic acid (u 980 cm, 1700 cm.1725 cm; NMR (approximately 10 percent solution in dcuterochloroform]:triplet at 0.868 (J 5.0 cycles/second). multiplets and at 1.05-2.058,2.05-2.708, 3.85-4.258, 5.45-5 .708. and a singlet at 6.108; elementalanalysis;

Found: C. 7234: H. 10.4%;

C2. ,H;".O requires C. 72.2; H. 10.4%

7-{ 5-( 3-hydroxydodecl -enyl )-2-0xocyclopentyllheptanoic acid (v,,,..,980 cm. 1700 cm, 1720 cm; NMR (approximately 10 percent solution indeuterochloroform): triplet at 0.898 (.1 5.5 cycles/second). multipletsat 1.558. 2.0-2.78, 5.578, broad multiplet at 4.158, and singlet at6.58; elemental analysis:

Found: 24 42 4 C. 73.0; requires C. 71.0; requires c. m; H. 9.9%

25 7-1S-(3-hydroxyhex-1-enyl)-2-oxocye1opentyllheptanoic acid [v,,,,,,980 cm", 1700 cm". 1720 cm; NMR (approximately 10 percent solution indeuterochloroform): triplet at 0.95 (.l 5.5 cycles/second). multipletsat 1.1-2.16. 2.0-2.68. 5.555, broad multiplet at 3.13-4.35, and singletat 7.18; elemental analysis;

C. 69.4; requires C. 71.6. requires Found: ei zm i H. 10.357[5-(3-hydroxy-6-methyloct-l-enyl)-2-oxocyclopentyll-heptanoic acid [u,,980 cm. 1700 cm", 1720 cm"; NMR (approximately 10 percent solution indeuterochloroform multiplets at 0.7-1.055, 1.05-2.75, 5.5-5.78, broadmultiplet at 4.1 18, and singlet at 6.855; elemental analysis:

Found: ("JIH m t C. 71.2: requires H. mm].

7-l5-(3-hydroxy-7-methyloct-l-enyl)-2-oxocyclopentyll-heptanoic acid[v,,,,,, 980 cm". 1700 cm. 1720 cm; NMR (approximately 10 percentsolution in deuteroehloroform): doublet at 0.98 (J 5.7 cycles/- second),multiplets at 1.05-2.08, 2.0-2.75, 5.6635, broad multiplet at 4.155, andsinglet at 6.585; elemental analysis:

Found: :1 fllt 4 C. 71.2; requires7-[5-(3-cyclohexyl-3-hydroxyprop-l-eny1)-2-oxocyclopentyH-heptanoic acid[u,,,,,, 980 cm, 1700 cm", 1725 cm; elemental analysis:

C. 7| .2. requires Found C. 68.5; H. 10.2%; (.MHMO requires C. 68 5; H.9.85; l.

The intermediate 7-( 7-alkenyll .4-dioxaspiro- [4,4lnon-6-yl) heptanoieacids were prepared as follows:

By proceeding in a manner similar to that hereinbefore described inExample 2(i) and 2(ii) for the preparation of7-{1.4-dioxa-7-(3-oxooct-1-enyl)spirol4.4lnon-6-yl}heptanoic acid butsubstituting the chloroheptana-Z-one used as a starting material by the-chloroheptan-quantities of 1-ch1orononan-2-one, 1 chloroundecan-Z-one.l-chlorohexan-Z-one. 1- chloropentan-Z-one.l-chloro-4-methylheptan-2-one. l-chloro-5-methylheptan-2-one. 1-chloro-6- methylheptan-Z-one. chlorohethyl eyclohexyl ketone andl-ch1oro-7-methoxyheptan-Z-one respectively. there were prepared, viathe intermediates:

2-oxononyltriphenylphosphonium chloride. m.p. 205-207C.,2-oxoundecyltriphenylphosphonium chloride. mp. 170C.2-oxohexyltriphenylphosphonium chloride. Zooxopentyltriphenylphosphoniumchloride. mp 159C. 4-methyl-2- oxoheptyltriphenylphosphonium chloride.

5-methyl-2-oxoheptyltriphenylphosphonium chloride.o-methyl-2-oxoheptyltriphenylphosphonium chloride. m.p. 160C.2-cyclohexyl-2-oxoethyltriphenylphosphonium chloride. m.p. l8l-183C. and7-methoxy-2-oxoheptyltriphenylphosphonium chloride, m.p. 100-102c.;octanoylmethylenetriphenylphosphorane. mp.

74-76C.. deeanoylmethylenetriphenylphosphorane. mp

74-76C.. pentanoylmethylenetriphenylphosphorane. m.p.

54-56C.. butyrylmethylenetriphenylphosphorane. m.p.

158-161C.. 3-methylhexanoylmethylenetriphenylphosphorane. m.p. 90-93C..4-methylhexanoylmethylenetriphenylphosphorane.

mp. -68C.. S-methylhexanoylmethylenetriphenylphosphorane,

m.p. 99-104C.. eyclohexylcarbonylmethylenetriphenylphosphorane.

m.p. 164l65C. and o-methoxyhexanoylmethylenetriphenylphosphorane;

6-( 7-hydroxyhepty1)-l .4-dioxa-7-( 3-oxodec-l enyl)spiro-[4.4]nonane,6-( 7-hydroxyhepty1)- 1 .4-dioxa7-( 3-oxododecl eny1)spiro-l4,4]nonane.6-(7-hydroxyheptyl)-1.4-dioxa-7-(3-oxohept-1- eny1)spiro-[4,4]nonane.6-(7-hydroxyheptyH-1.4-dioxa-7-( 3-oxohex-lenyl)spiro-[4.4]nonane.6-(7-hydroxyheptyl)-7-(5-methy1-3-oxooct-l-enyl)-1.4-dioxaspiro[4.4lnonane.6-(7-hydroxyheptyl)-7-(6-methyl-3-oxooct-l-enyl)-1.4-dioxaspiro[4.4lnonane.6-(7-hydroxyhepty1l-7-methyl-3-oxooct-1-eny1)-l.4-

dioxaspiro[4,4Inonane. 7-(3-cyclohexyl-3-oxoprop-I-enyIJ-6-(7-hydroxyheptyl )-1 ,4-dioxaspirol4.4 ]nonane and 6( 7-hydroxyheptyl )-7-(8-methoxy-3-oxooetl enyl)-l.4-dioxaspiro[4,4]nonane; these 7-alkenyl-6-hydroxyhepty1-1,4-dioxaspiro[4.4lnonanes were obtained in acrude form but all were pure enough to use as starting materials in thepreparation of the 7-(7-alkenyl-1,4-dioxaspiro- [4.4lnon-o-yhheptanoicacids} the following compounds: 7- {l .4-dioxa-7-( 3-oxodecl -enyl)spiro[4.4]nono-yll-heptanoie acid. u 1620 cm". 1660 cm". 1700 cm,

EXAMPLE 9 7-[ -1 3Adamantyl-3-hydroxyprop-l -enyl)2-oxocyclopentyll-heptanoic acid i. Preparation of7-(3-adamantyl3-oxoprop-l-enyl)-6-(7-hydroxyheptyH-l.4-dioxaspiro{4.4]nonane A mixtureot7-formyl-o-(7-hydroxyheptylJ-l.4-dioxaspiro[4.4]nonane [2.7 g:prepared as described in Example l(i\ and adamantylcarbonylmcthylenetriphenylphosphorane [4.38 g; prepared according to the method described byKucher. Coll. Czech. Chem. Comm. (I968 33, 88Ulinhexamethylphosphorustriamide (60 ml.) was heated on a steam bath for 4days. Diethyl ether was added to the cooled reaction mixture and thesolid which separated out was filtered off. The filtrate was washedtwice with water. dried over anhydrous sodium sulphate and evaporated togive crude 7-( 3-adamantyl3-oxoprop-l-cnyl)-6-(7- hydroxyheptyl I,4-dioxaspirol 4.4lnonane (u,,,,,, lhltl cm H180 cm). This material wasused for the next step. the preparation of 7{7-( 3-adamantyl-3oxoprop-l-enyl)-l.4-dioxaspirol4.4]non-byliheptanoic acid. withoutfurther purification being necessary. (ii) Preparation of7-(7-(3-adamantyl-S-oxoprop-lenyl l .4-dioxaspirol 4,4]non-fi-yl)heptanoie acid By proceeding in a similar manner to that describedabove in Example 2(ii) for the preparation of 7 {l.4- dioxa-7(3-oxooct-l -enyl )spiro[4.4lnon-6-yl) heptanoic acid. but substitutingthe appropriate quantity of 7-(F-adamantyl-3-oxoprop-l-enyl)6-(7-hydroxyheptyl)-l,4-dioxaspirol4,4lnonane for the 6-(7-hydroxyheptyl)-l.4dioxa-7-(3-oxooct-lenyl)spiro[4.4]nonane used asstarting material. there was prepared7-{7-(3-adamantyl-3-oxoprop-l-enyl)l.4-dioxaspirol4.4]non-6-yl}heptanoic acid. iii. Preparation of7-[ 53-adamantyl-3-hydroxyprop-lenyl)i-oxocyclopcntyllheptanoic acid Byproceeding in a similar manner to that described above in Example 2(iii)for the preparation of 7-[5-(3-hydroxyoct-l'enyl)-2-oxocyclopentyl]heptanoic acid, but substituting theappropriate quantity of 7-{7-(3- adamantyl-J-oxopropl -enyl )-l.4-dioxaspiroi 4.4 lnonoyl}-heptanoic acid for the 7-{l.4-dioxa-7-(3-oxooctl enyl) spiro[4.4]non-(i-yli heptanoic acid usedas starting material. there was prepared 7-( 5-( 3- adamantyl3-hydroxyprop-l-enyl)-2-oxocyclopentyl1- heptanoic acid (14 980 cm, 1630cm", 1700 cm. I730 cm; NMR (approximately 1U percent solution indeuterochloroform): multiplets at 1.985, 3.7-4.355, 5.2-5.755].

EXAMPLE 10 A solution of7-15-(3-cyclopentyl-3-hydroxyprop-lenyl)-2-oxocyclopentyllheptanoic acid(1.0 g.; prepared as described in Example 4) in ethanol (50 ml.) wascatalytically reduced with hydrogen at a pressure of 7 kg/cm and in thepresence of a 5 percent palla dium on charcoal catalyst (0.5 g.) at roomtemperature for 3 hours. The catalyst was then filtered off and theethanol evaporated to give 7-[5-(3-cyclopentyl-3-hydroxyprop-l-yl)-2-oxocyclopentyllheptanoic acid (0.8 g.)v

A pure sample of the acid was obtained by separation using preparativethin-layer chromatography on silica gel. using as the eluent a 40:40:lmixture by volume of ethyl acetate, cyclohexane and formic acid [14 1700cm, 1720 cm"; NMR (approximately l0 percent solution indeuterochloroform): multiplets at 0.9-2.058, 2.052.68, 3.2-3.73, and asinglet at (1.045; elemental analysis:

Found: C. 70.7. H. ltltl i; H O. requires C, 7 .t); H. Hill)? EXAMPLE 1l 7[ 5-( 3 Hydroxyoct l enyl)-3-methyl-Z-oxocyclopentyll-heptanoic acid.i. Preparation of 3oxo-2-[7-(2-tetrahydropyranyloxylheptyllcyclopentanecarbonitrile3.4-Dihydro2H-pyran (7.3 g.) was added dropwise at 40C. with stirring toa mixture of 2-(7- hydroxyheptyl)-3-oxocyclopentanecarbonitrile [10 g;prepared as described in Example l(ii)] and concentrated hydrochloricacid (4 drops). The temperature was allowed to rise to C. and wasmaintained at 65C. for 1 hour. The solution was cooled and benzene (50ml.) was added. The solution was washed with aqueous sodium bicarbonateand then water. and dried over sodium sulphate. The solvent was removedin vacuo to give crude 3-oxo-2-[7-(2-tetrahydropyranyloxylheptyl]cyclopentanecarbonitrile 15 g.). This materialwas used for the next step, the preparation of 4-ethoxalyl-3-ox0-2-{7(2- tetrahydropyranyloxyheptyl]- cyclopentaneearbonitrile. withoutfurther purification being necessary. ii. Preparation of4-ethoxalyl-3-oxo-2-[ 7-( 2-tetrahydropyranyloxy)heptyl]cyclopentanecarbonitrile An ice-coldsolution of 3-oxo-2-[ 7 2'tetrahydropyranyloxy)heptyllcyclopentanecarbonitrile (15 g.) and diethyloxalate (15.9 g.) in dry benzene ml.) was added to dry sodium methoxide(5.9 g. The mixture was then left to stand at room temperature for 24hours. Ice-water was then added. and the layers separated. The aqueouslayer was washed with benzene and the benzene solutions combined. lt wasthen added to 30 percent aqueous sodium dihydrogen phosphate solutionml.) at 0C. The combined benzene solutions were extracted four timeswith ice-cold 4 percent aqueous sodium hydroxide solution. and thecombined alkaline extracts added to the aqueous sodium dihydrogenphosphate solution. stirred at C. for minutes. and then extracted withdiethyl ether. The combined ethereal extracts were washed with water anddried over sodium sulphate. The solvent was removed in vacuo to givecrude 4-ethoxalyl-3-oxo 2-[7-(2-tetrahydropyranyloxy)heptyl]cyclopentanecarbonitrile (11.2 g.). u,,,,,,I720 cm", l670 cm, l605 cm". iii Preparation of 4-methyl-3-oxo-2-l7-(2-tetrahydropyranyloxy)heptyl]cyclopentanecarbonitrile A mixture of4-ethoxalyl-3-oxo-2-l7-(2-tetrahydropyranyloxy)heptyl]cyclopentanecarbonitrile (11.2 g). anhydrouspotassium carbonate (22 g. methyl iodide (67 ml). and undried acetone(450 ml.) was stirred and heated at reflux for 22 hours. The mixture wasthen cooled and filtered. and the filtrate concentrated in vacuo. Waterwas added to the residue and the mixture extracted with diethyl ether.The combined ethereal extracts were washed successively with 2N aqueoussodium hydroxide solution and water, and then dried over sodiumsulphate. The diethyl ether was removed in vacuo to give crude4-methyl-3-oxo-2-[7-(2-tetrahydropyranyloxy)heptyl]cyclopentanecarbonitrilc (8.3 g.). u i730cm". This material was used for the next step, the preparation of 2-(7-hydroxyheptyl)-4-methyl-3-oxocyclopentanecarbonitrile. without furtherpurification being necessaary. iv. Preparation of2-(7-hydroxyheptyl)-4-methyl-3- oxocyclopentanecarbonitrile 60 percentAqueous perchloric acid solution (6 drops) was added to a solution of4-methyl-3-oxo-2-{7-(2-tetrahydropyranyloxy)heptyllcyclopentanecarbonitrile (8.3 g.) in dryethanol (35 ml.). After 24 hours chloroform was added, and the solutionwashed successively with 2N aqueous sodium carbonate solution andsaturated aqueous sodium chloride solution. and dried over sodiumsulphate. The solvents were removed in vacuo. and the residue distilledunder pressure to give 2-( 7-hydroxyheptyl)-4-methyl-3-oxocyclopentanecarbonitrile (3.5 g.). b.p. l40200C./0.l5mm.Hg v,,,,,, 1730 cm elemental analysis:

C. 70.2; requires L'. 71.0: requires Found: CZIHIWOJ via theintermediates:

7-cyano6-( 7-hydroxyheptyl t 9-methyl-l .4-dioxaspiro-[4,4]nonane,

30 7-form vl-6-( 7-hydroxheptyl )-9-methyll .4dioxaspiro-[ 4.4 ]nonane.6-( 7-hydroxyheptyl )-9-methyl-7-( 3-oxooctl -enyl l.4-dioxaspiro[4.4lnonane and 7{9-methyll .4-dioxa-7-( S-oxooct- 1enyl)spiro[4.4]non-6-yl}heptanoic acid.

EXAMPLE [27-[2-Methoxyimino-5-(3-hydroxyoct-l-enyl)cyclopentyl]-heptanoic acid i.Preparation of 2-(7-hydroxyheptyll-3-methoxyiminocyclopentanecarbonitrile A mixture of2-(7-hydroxyheptyl)-3-oxocyclopentanecarbonitrile [5.0 g; prepared asdescribed in Example l(ii)], methoxylamine hydrochloride (2g) andpyridine (6. 1 ml.) was left to stand at ambient temperature for 24hours. Pyridine was removed in vacuo and water (20 ml.) was added. Themixture was extracted with diethyl ether and the extract dried overmagnesium sulphate. The solvent was removed by evaporation and theresidue was distilled under reduced pressure to give2-(7-hydroxyheptyl)-3-methoxyiminocyclopcntanecarbonitrile (4.33 g. hp.l5U-l9()C./0.t)7 mmHg. [1 1050 cm. 2250 cm'].

ii. Preparation of 3-formyl-2-( 7-hydroxyheptyl)methoxyiminocyclopentane In a similar manner to thatdescribed in Example l(iv) for the preparation of 7-formyl-6-(7-hydroxyheptyU-l .4-dioxaspiro[4.4]nonanc. but substituting theappropriate quantity of2-( 7-hydroxyhcptyl3-methoxyiminocyclopentanecarbonitrile for the 7- cyano-6-(7-hydroxyheptyl )-l .4-dioxaspirol 4.4 ]nonanc used as startingmaterial. there was prepared 3-formyl- 2-( 7-hydroxyheptyl)methoxyiminocyclopentane [1/ "ML 1050 cm". 1720 cm". 2750 cm].

iii. Preparation of 2 (7hydroxyheptyl)-3-(3-oxooctlenyl)methoxyiminocyclopentane In a similar manner to that described inExample 2(i). for the preparation of 6-(7'hydroxyheptyH-l.4-dioxa-7-(3-oxooct-l enyl)spiro[4.4]nonane. but substituting theappropriate quantity of 3-formyl-2-(7-hydroxyheptyl)methoxyiminocyclopentane for the 7- formyl-6-(7-hydroxyheptyl )-l .4-dioxaspirol 4,4]nonane used as starting material,there was prepared 2-( 7- hydroxyheptyl )-3-( 3-oxooctl -enyl)methoxyiminocyclopentane [u,,,,,, 1050 cm", l620 cm. [660 cm") iv.Preparation of 7-[2methoxyimino-5-(3-oxooet-lenyllcyclopentyl]heptanoicacid In a similar manner to that described in Example ](vi) for thepreparation of 741,4-dioxa-7-(3-oxo-4-methyloct-lenyl)spiro[4.4]non-6-yl} -heptanoic acid. but substitutingthe appropriate quanity of 2-(7- hydroxyheptyl )-3-( 3-oxooctl -enyl)-methoxyiminocyclopentane for the 6-(7-hydroxyheptyl)-l,4-dioxa-7-(3-oxo-4-methyloct-l-enyl)spiro[4.4]nonane used as starting material.there was prepared 7-[2- methoxyimino-5-( 3-oxooctlenyl )cyclopentyllheptanoic acid.

(v) Preparation of 7-[2-methoxyimino-5-(3- hydroxyoct-lenyl)cyclopentyl]heptanoic acid A solution of sodium borohydride(0.222g.) in 0.2N aqueous sodium hydroxide (2ml.) was added dropwise toa solution of 7-[2-methoxyimino-5-(3oxooct-lenyl)-cyclopentyl]heptanoicacid (0.84 g.) in ethanol (50 ml.) and N sodium hydroxide (2 ml. Theresulting solution was stirred for 20 hours and then the ethanol removedin vacuo. Water (10 ml.) was added and the resulting solution was washedwith diethyl ether. The aqueous layer was then covered with a layer ofdiethyl ether and acidified to pH i by the dropwise addition ofconcentrated hydrochloric acid. The ethereal layer was separated and theaqueous layer was extracted twice more with diethyl ether. The combinedethereal extracts were dried over magnesium sulphate and the solventevaporated to give 7-[2-methoxyimino5-( 3-hydroxyoct-l-enyl)cyclopentyllheptanoic acid hemihydrate [u 1050 cm.1700 cm"; elemental analysis:

Found: C, 67.5; H. 9.). N 3.3l i. H lNO rzH O requires C. 67.3. H. I02;

NMR (approximately 10 percent solution in deuterochloroform): multipletsat 5.42-5.708, 3.35-4.355, 205 3.06, 1.05-1.055, triplet at 0.875 (J 50cycles/- second). singlet at 3.826 and a broad singlet at 6114-7455].

EXAMPLE 13 Preparation of 7-[ 3-acetoxy-4methyloctl -enyl)-'.Z-oxocyclopentyllheptanoic acid.

A solution of 7-lS-t3-hydroxy-4-methyloct-lenyl)--Z-oxocyclopentyllheptanoic acid {0.34 g; prepared described in Example 1(vii)lin dry pyridine (ml) was treated with acetic anhydride (l0 ml.)and the re sulting solution was allowed to stand at ambient temperaturefor 3 days and then diluted with water with external cooling by an icebath. The resulting aqueous solution was extracted twice with diethylether and the combined extracts washed with dilute hydrochloric acid andwater, then dried over magnesium sulphate. Evaporation in vacuo gave7-l5-(3-acetoxy-4- methyloct' l -enyl )-2-oxocyclopentyllheptanoic acid(0.37 g.). which was purified by preparative thin layer chromatographyon silica gel using a 40:40:l mixture by volume of ethyl acetate.cyclohexane and formic acid as eluent.

Elemental analysis:

Found: 7U l. H. ll),l) l;; C H U requires C. 70 (I. H. 9.79

u 975 cm". I240 cm, l700 cm". l7l5 cm. 1725 cm".

EXAMPLE [4 Methyl 7-[ 5-( 3-cylcohexyl3-hydroxyprop l -enyl i-Z-oxocyclopentyl heptanoate 32 deuterochloroform singlets at 3.685, 4.305and a multiplet at 5.404.705].

EXAMPLE [5 By proceeding in a similar manner to that described above inExample 14 for the preparation of methyl 7- l 5-(3-cyclohexyl-3-hydroxyprop-1-enyl)2- oxocyclopentyllheptanoate. butsubstituting the appropriate quantities of 7-[5-(3-cyclopentyl-3hydroxyprop-l-enyl)-2-oxocyelopentyllheptanoic acid and7-[5-(3-hydroxydodec-l-enyl)-2-0xocyclopentyl]- heptanoic acid (preparedas described in Examples 4 and 8 respectively) for the7-[5-(3-eyclohexyl3- hydroxyprop-l-enyl)-2-oxocyclopentyllheptanoic acidused as starting material. there were prepared methyl7-l5-(3-cyclopentyl-3-hydroxyprop-l-enyl)-2- oxocyclopentyllheptanoate(v,,,,,, 980 cm. 1725 cm. 3450 cm) and methyl 7-[5-(3-hydroxydodec-lenyl)-2-oxocyclopentyllheptanoate (1 980 cm. 1730 cm. 3470 cm";elemental analysis:

Found C. 73.1; H, 10.85;; H G requires C. 73.4. H, i019";

EXAMPLE l6 N-methyl-7-[ 5-( 3-hydroxydodecl -enyl )"loxocyclopentyl-heptan0amide A mixture of methyl 7-l5-(3 hydroxydodec-l-enyl)-2-oxocyclopentyllheptanoate (0.30 g.; prepared as described in Examplel5). N methylformamide (1.9 g.) and anhydrous sodium methoxide (0.06 g.)was heated at C. for one day. After cooling. ice-cold 5 percent aqueoushydrochloric acid was added and the mixture was extracted withchloroform. The chloroform extract was washed with water and dried oversodium sulphate. The chloroform was removed in vacuo. and the residuewas purified by preparative thin-layer chromatography on silica gelusing a 5:3 mixture by volume of benzene and dioxane as the eluent. togive N-methyl7-[5-(3- hydroxydodec-l -enyl )-2-oxocyclopentyllheptanoamide (0.09 g.) [v,,,,,, 980 cm"'. 1560 cm. [650 cm, l720 cm,3300 cm"-; NMR (approximately 10 per cent solution indeuterochloroform): triplet at 0.866, (J 5.0 cycles/second). multipletsat l.05-l.956, 1.95-2.68, 5.2-6.25. doublet at 3.775(] 4.5 cycles/-second). and a broad multiplet at 3.754.258].

EXAMPLE l7 By proceeding in a similar manner to that described above inExample 14 for the preparation of methyl 7-[5-(3-cyclohexylJ-hydroxyprop-lenyl)-2- oxocyclopentyl ]heptanoate. butsubstituting the appropriate quantity of diazoheptane (prepared asdescribed by Porrnale, Plisko and Danilov, Org.Chem. U.S.S.R. (EnglishEdn.). I965. l. l788) for the diazomethane used as starting material.there was prepared heptyl 7- [5-(3-eyclohexyl-3-hydroxyprop-l -enyl)-2-oxocyclopentyllheptanoate [v,,,.,, 980 cm". 1730 cm". 3450 cm, NMR(approximately l0 percent solution in deuterochloroform): multiplets at5.45-5.658, 3.7-4. l5, 1.05-2.76, triplets at 4.066 (J 60 cycles)second) and 0.9l8 (.l 5.5 cycles/secondl].

The present invention includes within its scope pharmaceuticalcompositions which comprise at least one compound of the above-mentionednovel class of cyclopentane derivatives of general formula I or, when Rrepresents a carboxy group. non-toxic salts thereof. together with apharmaceutical carrier or coating. ln clinical practice the novelcompounds of the present invention will normally be administered orally.rectally. vaginally or parenterally.

Solid compostions for oral administration include compressed tablets,pills. dispersible powders. and granules. In such solid compositions oneor more of the active compounds is. or are. admixed with at least oneinert diluent such as calcium carbonate, potato starch. alginic acid. orlactose. The compositions may also comprise. as is normal practice.additional substances other than inert diluents. e.g. lubricatingagents. such as magnesium stearate. Liquid compositions for oraladministraton include pharamceutically-acceptable emulsions. solutions,suspensions. syrups and elixirs containing inert diluents commonly usedin the art. such as water and liquid paraffin. Besides inert diluentssuch compositions may also comprise adjuvants. such as wetting andsuspending agents. and sweetening. flavoring. perfuming and preservingagents. The compositions according to the invention. for oraladministraton. also include capsules of absorbable material such asgelatin containing one or more of the active substances with or withoutthe addition of diluents or excipients.

Solid compositions for vaginal administration include pessariesformulated in manner known per se and containing one or more of theactive compounds.

Solid compositions for rectal adminstration include suppositoriesformulated in manner known per se and containing one or more of theactive compounds.

Preparations according to the invention for parenteral administrationinclude sterile aqueous or nonaqueous solutions. suspensions. oremulsions. Examples of non-aqueous solvents or suspending media arepropylene glycol. polyethylene glycol. vegetable oils such as olive oil.and injectable organic esters such as ethyl oleate. These compositionsmay also include adjuvants such as preserving. wetting. emulsifying anddispersing agents. They may be sterilised. for example. by filtrationthrough a bacteria-retaining filter. by incorporation of sterilisingagents in the compositions. by irradiation. or by heating. They may alsobe manufactured in the form of sterile solid compositions. which can bedissolved in sterile water or some other sterile injectable mediumimmediately before use.

The percentage of active ingredient in the compositions of the inventionmay be varied. it being necessary that it should constitute a proportionsuch that a suitable dosage for the therapeutic effect desired shall beobtained. Obviously several unit dosage forms may be administered atabout the same time. In general. the preparations should normallycontain at least 0025 percent by weight of active substance whenrequired for administration by injection; for oral administration thepreparations will normally contain at least 0.1% by weight of activesubstance. The dose employed depends upon the desired therapeuticeffect. the route of administration and the duration ofthe treatment. lnthe adult. the doses are generally between 0.02 and 2.0 mg. by aerosoladministration as bronchodilators. between 0.0002 and 2.0 mgjkg. bodyweight by intravenous administration. preferably by intravenous infusionat a rate of between 0.000] and [.0 mg./kg. body weight! minute ashypotensives. between 0.0(ll and 0.3 mgjkg. body weight orally asinhibitors of gastric acid secretion. and between 0.01 and L mg./kg bodyweight by intravenous administration. preferably by intravenous infusionat a rate of between 0.02 and 20 ting/kg. body weight/minute asstimulators of uterine contraction. If necessary these doses may berepeated as and when required.

The compounds of general formula I and. when R represents a carboxygroup. non-toxic salts thereof may be administered orally asbronchodilators by any method known per se for administration byinhalation of drugs which are not themselves gaseous under normalconditions of administration. Thus. a solution of the active ingredientin a suitable pharmaceuticallyacceptable solvent. for example water. canbe nebulized by a mechanical nebulizer. for example a Wright Neublizer.to give an aerosol of finely-divided liquid particles suitable forinhalation. Advantageously. the solution to be nebulized is diluted andpreferably aqueous. solutions containing from 0.2 to 20 mg.. andpreferably 0.2 to 5.0 mg.. of active ingredient per ml. of solutionbeing particularly suitable. The solution may contain stabilizing agentssuch as sodium bisulphite and buffering agents to give it an isotoniccharacter. e.g. sodium chloride. sodium citrate and citric acid.

The active ingredients may also be administered orally by inhalation inthe form of aerosols generated from self-propelling pharmaceuticalcompositions. Compositions suitable for this purpose may be obtained bydissolving or suspending in finelydivided form. preferably micronized toan average particle size of less than 5 microns. the active ingredientsin pharmaceutically-acceptable solvents. e.g. ethanol. which areco-solvents assisting in dissolving the active ingredients in thevolatile liquid propellants hereinafter described. orpharmaceutically-acceptable suspending or dispersing agents. for examplealiphatic alcohols such as oleyl alcohol. and incorporating thesolutions or suspensions obtained with pharmaceuticallyacceptablevolatile liquid propellants. in conventional pressurized packs which maybe made of any suitable material. e.g. metal. plastics or glass.adequate to withstand the pressures generated by the volatile propellantin the pack. Pressurized pharmaceutically-acceptable gases. such asnitrogen. may also be used as propellants. The pressurized pack ispreferably fitted with a metered valve which dispenses a controlledquantity of the self-propelling aerosol composition as a single dose.

Suitable volatile liquid propellants are known in the art and includefluorochlorinated alkanes containing from one to four. and preferablyone or two. carbon atoms. for example dichlorodifluoromethane.dichlorotetrafluoroethane. trichloromonofluoromethane.dichloromonofluoromethane and monochlorotrifluoromethane. Preferably.the vapour pressure of the volatile liquid propellant is between about25 and 65 pounds. and more especially between about 30 and 55 pounds.per square inch gauge at 21C. As is well-known in the art. volatileliquid propellants of different vapour pressures may be mixed in varyingproportions to give a propellant having a vapour pressure appropriate tothe production of a satisfactory aerosol and suitable for the chosencontainer. For example dichlorodifluoromethane (vapor pressure poundsper square inch gauge at 2lC.) and dichlorotetrafluoroethane (vapourpressure 28 pounds per square inch gauge at 2lC.) may be mixed invarying proportions to give propellants having vapour pressuresintermediate between those of two constituents 35 eg a mixture ofdichlorodifluoromethane and di chlorotetrafluoroethane in theproportions 38:62 respectively by weight has a vapour pressure of 53pounds per square inch gauge at 21C.

The self-propelling pharmaceutical compositions may be prepared bydissolving the required quantity of active ingredient in the co-solventor combining the required quantity of active ingredient with a measuredquantity of suspending or dispersing agent. A measured quantity of thiscomposition is then placed in an open container which is to be used asthe pressurized pack. The container and its contents are then cooledbelow the boiling temperature of the volatile propellant to be used. Therequired quanity of liquid propellant. cooled below its boilingtemperature, is then added and the contents of the container mixed. THecontainer is then sealed with the required valve fitting. withoutallowing the temperature to rise above the boiling temperature of thepropellant. The temperature of the sealed container is then allowed torise to ambient with shaking to ensure complete homogeneity of thecontents to give a pressurized pack suitable for generating aerosols forinhalation. Alternatively. the co-solvent solution of the activeingredient or combination of active ingredient and suspending ordispersing agent is placed in the open container. the container sealedwith a valve. and the liquid propellant introduced under pressure.

Means for producing self-propelling compositions for generating aerosolsfor the administration fo medicaments are. for example. described indetail in US. Pat. Nos. 2.868.691 and 3.095.355.

Preferably. the self-propelling pharmaceutical compositions according tothe present invention contain from 0.2 to 20 mg. and more particularly0.2 to 5.0 mg. of active ingredient per ml. of solution or suspension.it is important that the pH of solutions and suspensions used. accordingto the present invention. to generate aerosols should be kept within therange 3 to 8 and preferable that they should be stored at or below 4C..to avoid pharmacological deactivation of the active ingredient.

ln carrying out the present invention. the means of producing an aerosolfor inhalation should be selected in accordance with thephysico-chemical properties of the active ingredient.

By the term pharmaceutically-acceptable" as applied in thisspecification to solvents suspending or dis persing agents. propellantsand gases is meant solvents. suspending or dispersing agents.propellants and gases which are non-toxic when used in aerosols suitablefor inhalation therapy.

It is highly desirable that the aerosols should have a particle sizeless than about 10 microns and preferably less than 5 microns. forexample between 0.5 and 3 microns. to ensure effective distribution tovery narrow bronchioles. Preferably. administration is by means ofdevices enabling controlled quantities of the active in gredients to beadministered, for example by means of the metered valves hereinbeforementioned.

The following Examples illustrate pharmaceutical compositions accordingto the invention.

EXAMPLE 1% 7-[5-( 3-Hydroxy-4methyloctl-enyl)-2-oxocyclopentyllheptanoic acid (300 mg.) was dissolved in ethanol t lml.) and the solution obtained was added to an aqueous solution ([2 ml.containing sodium carbonate (50 mg). Aqueous sodium chloride solution(0.9 percent w/v. Zml.) was then added to give a final volume of 15 ml.The solution was then sterilized by passage through a bacteria-retainingfilter and placed in L5 ml. portions in 5 ml. ampoules. to give 30 mg.of the heptanoic acid derivative (in the form of its sodium salt) perampoule. The contents of the ampoules were freeze-dried and the ampoulessealed. Dissolution of the contents of an ampoule in a suitable volume.e.g. 2 ml. of sterile water or physiological saline gave a solutionready for administration by injection.

EXAMPLE l9 7[ 5-( 3-Hydroxy-5-methylhexl -enyl )-2-oxocy'clopentyllheptanoic acid (300 mg.) was dissolved in ethanol (1 ml.) andthe solution obtained was added to an aqueous solution (12 ml.)containing sodium carbonate (50 mg.). Aqueous sodium chloride solution(0.9 percent w/v, Zml.) was then added to give a final volume of l5 ml.The solution was then sterilized by passage through a bacteria-retainingfilter and placed in L5 ml. portions in 5 ml. ampoules. to give 30 mg.of the heptanoic acid derivative (in the form ofits sodium salt) perampoule. The contents of the ampoules were freeze-dried and the ampoulessealed. Dissolution of the contents of an ampoule in a suitable volume.e.g. 2 ml. of sterile water or physiological saline gave a solutionready for administration by injection.

We claim:

I. A 2 -hydroxyalkyl)cyclopentanecarbaldehyde of the formula:

wherein R represents alkyl of l through 6 carbon atoms or hydrogen. nrepresents 5. 6, 7, or 8. and the symbols R represent identical alkylgroups of l through 6 carbon atoms or together form ethylene.

2. A 2-hydroxyalkyl)cyclopentanecarbaldehyde of the formula:

7 (CH2 cn on M CIIO

1. A 2 -HYDROXALKYL)CYCLOPENTANECARBALDEHYSE OF THE FORMULA:
 2. A2-hydroxyalkyl)cyclopentanecarbaldehyde of the formula:
 3. Thecyclopentanecarbaldehyde according to claim 2 which is7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro(4,4)nonane.
 4. Thecyclopentanecarbaldehyde according to claim 2 which is7-formyl-6-(7-hydroxyheptyl)-9-methyl-1,4-dioxaspiro(4,4)nonane.